Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†
Identifieur interne : 000871 ( Istex/Corpus ); précédent : 000870; suivant : 000872Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†
Auteurs : Alon Zilka ; Guy Landau ; Oren Hershkovitz ; Noga Bloushtain ; Ahuva Bar-Ilan ; Fabrice Benchetrit ; Eyal Fima ; Toin H. Van Kuppevelt ; John T. Gallagher ; Sharona Elgavish ; Angel PorgadorSource :
- Biochemistry [ 0006-2960 ] ; 2005.
Abstract
NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors (NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate. Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity but reduced its binding to tumor cells with a 10−100 fold lower KD when tested for direct binding to heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and cancers.
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DOI: 10.1021/bi051241s
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work.</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Landau, Guy" sort="Landau, Guy" uniqKey="Landau G" first="Guy" last="Landau">Guy Landau</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> A.Z. and G.L. contributed equally to this work.</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Hershkovitz, Oren" sort="Hershkovitz, Oren" uniqKey="Hershkovitz O" first="Oren" last="Hershkovitz">Oren Hershkovitz</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Bloushtain, Noga" sort="Bloushtain, Noga" uniqKey="Bloushtain N" first="Noga" last="Bloushtain">Noga Bloushtain</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Bar Ilan, Ahuva" sort="Bar Ilan, Ahuva" uniqKey="Bar Ilan A" first="Ahuva" last="Bar-Ilan">Ahuva Bar-Ilan</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Benchetrit, Fabrice" sort="Benchetrit, Fabrice" uniqKey="Benchetrit F" first="Fabrice" last="Benchetrit">Fabrice Benchetrit</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Fima, Eyal" sort="Fima, Eyal" uniqKey="Fima E" first="Eyal" last="Fima">Eyal Fima</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Van Kuppevelt, Toin H" sort="Van Kuppevelt, Toin H" uniqKey="Van Kuppevelt T" first="Toin H." last="Van Kuppevelt">Toin H. Van Kuppevelt</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> University Medical Center.</mods:affiliation></affiliation></author><author><name sortKey="Gallagher, John T" sort="Gallagher, John T" uniqKey="Gallagher J" first="John T." last="Gallagher">John T. Gallagher</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> University of Manchester.</mods:affiliation></affiliation></author><author><name sortKey="Elgavish, Sharona" sort="Elgavish, Sharona" uniqKey="Elgavish S" first="Sharona" last="Elgavish">Sharona Elgavish</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> The Hebrew UniversityHadassah Medical School.</mods:affiliation></affiliation></author><author><name sortKey="Porgador, Angel" sort="Porgador, Angel" uniqKey="Porgador A" first="Angel" last="Porgador">Angel Porgador</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:5FAA5D798F3882D8996FDF98C2E4917BAC44185C</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1021/bi051241s</idno><idno type="url">https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000871</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000871</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural
Cytotoxicity Receptor NKp46<ref type="bib" target="#bi051241sAF2">†</ref></title><author><name sortKey="Zilka, Alon" sort="Zilka, Alon" uniqKey="Zilka A" first="Alon" last="Zilka">Alon Zilka</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> A.Z. and G.L. contributed equally to this work.</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Landau, Guy" sort="Landau, Guy" uniqKey="Landau G" first="Guy" last="Landau">Guy Landau</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> A.Z. and G.L. contributed equally to this work.</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Hershkovitz, Oren" sort="Hershkovitz, Oren" uniqKey="Hershkovitz O" first="Oren" last="Hershkovitz">Oren Hershkovitz</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Bloushtain, Noga" sort="Bloushtain, Noga" uniqKey="Bloushtain N" first="Noga" last="Bloushtain">Noga Bloushtain</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Bar Ilan, Ahuva" sort="Bar Ilan, Ahuva" uniqKey="Bar Ilan A" first="Ahuva" last="Bar-Ilan">Ahuva Bar-Ilan</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Benchetrit, Fabrice" sort="Benchetrit, Fabrice" uniqKey="Benchetrit F" first="Fabrice" last="Benchetrit">Fabrice Benchetrit</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Fima, Eyal" sort="Fima, Eyal" uniqKey="Fima E" first="Eyal" last="Fima">Eyal Fima</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation></author><author><name sortKey="Van Kuppevelt, Toin H" sort="Van Kuppevelt, Toin H" uniqKey="Van Kuppevelt T" first="Toin H." last="Van Kuppevelt">Toin H. Van Kuppevelt</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> University Medical Center.</mods:affiliation></affiliation></author><author><name sortKey="Gallagher, John T" sort="Gallagher, John T" uniqKey="Gallagher J" first="John T." last="Gallagher">John T. Gallagher</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> University of Manchester.</mods:affiliation></affiliation></author><author><name sortKey="Elgavish, Sharona" sort="Elgavish, Sharona" uniqKey="Elgavish S" first="Sharona" last="Elgavish">Sharona Elgavish</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> The Hebrew UniversityHadassah Medical School.</mods:affiliation></affiliation></author><author><name sortKey="Porgador, Angel" sort="Porgador, Angel" uniqKey="Porgador A" first="Angel" last="Porgador">Angel Porgador</name><affiliation><mods:affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation><affiliation><mods:affiliation> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="ISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2005</date><date type="published">2005</date><biblScope unit="vol">44</biblScope><biblScope unit="issue">44</biblScope><biblScope unit="page" from="14477">14477</biblScope><biblScope unit="page" to="14485">14485</biblScope></imprint><idno type="ISSN">0006-2960</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2960</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors (NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate. Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity but reduced its binding to tumor cells with a 10−100 fold lower KD when tested for direct binding to heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and cancers.</div></front></TEI><istex><corpusName>acs</corpusName><keywords><teeft><json:string>heparin</json:string><json:string>sulfate</json:string><json:string>heparan</json:string><json:string>tumor cell</json:string><json:string>receptor</json:string><json:string>oligomers</json:string><json:string>mutation</json:string><json:string>heparan sulfate</json:string><json:string>fibronectin</json:string><json:string>biol</json:string><json:string>biochemistry</json:string><json:string>chem</json:string><json:string>biacore</json:string><json:string>epitope</json:string><json:string>putative</json:string><json:string>sulfate binding 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dichroism</json:string><json:string>natural killer cell</json:string><json:string>noncharged amino acid</json:string><json:string>membranal heparan sulfate</json:string><json:string>binding</json:string></teeft></keywords><author><json:item><name>ZILKA Alon</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>A.Z. and G.L. contributed equally to this work.</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>LANDAU Guy</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>A.Z. and G.L. contributed equally to this work.</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>HERSHKOVITZ Oren</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>BLOUSHTAIN Noga</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>BAR-ILAN Ahuva</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>BENCHETRIT Fabrice</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>FIMA Eyal</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string></affiliations></json:item><json:item><name>VAN KUPPEVELT Toin H.</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>University Medical Center.</json:string></affiliations></json:item><json:item><name>GALLAGHER John T.</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>University of Manchester.</json:string></affiliations></json:item><json:item><name>ELGAVISH Sharona</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>The Hebrew UniversityHadassah Medical School.</json:string></affiliations></json:item><json:item><name>PORGADOR Angel</name><affiliations><json:string>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</json:string><json:string>Ben Gurion University of the Negev.</json:string><json:string>To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</json:string></affiliations></json:item></author><arkIstex>ark:/67375/TPS-XC1SB6GX-4</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors (NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate. Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity but reduced its binding to tumor cells with a 10−100 fold lower KD when tested for direct binding to heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and cancers.</abstract><qualityIndicators><refBibsNative>false</refBibsNative><abstractWordCount>236</abstractWordCount><abstractCharCount>1534</abstractCharCount><keywordCount>0</keywordCount><score>9.832</score><pdfWordCount>7190</pdfWordCount><pdfCharCount>44322</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><pdfWordsPerPage>799</pdfWordsPerPage><pdfText>true</pdfText></qualityIndicators><title>Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†</title><genre><json:string>research-article</json:string></genre><host><title>Biochemistry</title><language><json:string>unknown</json:string></language><issn><json:string>0006-2960</json:string></issn><eissn><json:string>1520-4995</json:string></eissn><volume>44</volume><issue>44</issue><pages><first>14477</first><last>14485</last></pages><genre><json:string>journal</json:string></genre></host><ark><json:string>ark:/67375/TPS-XC1SB6GX-4</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - biochemistry & molecular biology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - biochemistry & molecular biology</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Biochemistry</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string></inist></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1021/bi051241s</json:string></doi><id>5FAA5D798F3882D8996FDF98C2E4917BAC44185C</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/bundle.zip</uri></json:item><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/fulltext.txt</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural
Cytotoxicity Receptor NKp46<ref type="bib" target="#bi051241sAF2">†</ref></title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>American Chemical Society</publisher><availability><licence>Copyright © 2005 American Chemical Society</licence><p>American Chemical Society</p></availability><date type="published">2005</date><date type="Copyright" when="2005">2005</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural
Cytotoxicity Receptor NKp46<ref type="bib" target="#bi051241sAF2">†</ref></title><author xml:id="author-0000"><persName><surname>Zilka</surname><forename type="first">Alon</forename></persName><note place="foot" n="bi051241sAF3"><ref>‡</ref><p>
A.Z. and G.L. contributed equally to this work.</p></note><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0001"><persName><surname>Landau</surname><forename type="first">Guy</forename></persName><note place="foot" n="bi051241sAF3"><ref>‡</ref><p>
A.Z. and G.L. contributed equally to this work.</p></note><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0002"><persName><surname>Hershkovitz</surname><forename type="first">Oren</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0003"><persName><surname>Bloushtain</surname><forename type="first">Noga</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0004"><persName><surname>Bar-Ilan</surname><forename type="first">Ahuva</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0005"><persName><surname>Benchetrit</surname><forename type="first">Fabrice</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0006"><persName><surname>Fima</surname><forename type="first">Eyal</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note></author><author xml:id="author-0007"><persName><surname>van Kuppevelt</surname><forename type="first">Toin H.</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF5"><ref>‖</ref><p>
University Medical Center.</p></note></author><author xml:id="author-0008"><persName><surname>Gallagher</surname><forename type="first">John T.</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF6"><ref>⊥</ref><p>
University of Manchester.</p></note></author><author xml:id="author-0009"><persName><surname>Elgavish</surname><forename type="first">Sharona</forename></persName><affiliation><orgName type="department">Department of Microbiology and Immunology</orgName><orgName type="department">Faculty of Health Sciences</orgName><orgName type="institution">and Cancer Research Center</orgName><orgName type="institution">Ben Gurion University of the Negev</orgName><address><addrLine>Beer Sheva 84105</addrLine><country key="IL" xml:lang="en">ISRAEL</country><addrLine>Department of Biochemistry</addrLine><addrLine>University Medical Center</addrLine><addrLine>NCMLS</addrLine><addrLine>Nijmegen</addrLine><addrLine>The Netherlands</addrLine><addrLine>Department of Medical Oncology</addrLine><addrLine>University of Manchester</addrLine><addrLine>Cancer Research UK</addrLine><addrLine>Christie</addrLine><addrLine>Hospital NHS Trust</addrLine><addrLine>Manchester M204BX</addrLine><addrLine>United Kingdom</addrLine><addrLine>and The Bioinformatics Unit</addrLine><addrLine>The Hebrew UniversityHadassah Medical School</addrLine><addrLine>Jerusalem 91120</addrLine><country key="IL" xml:lang="en">ISRAEL</country></address></affiliation><note place="foot" n="bi051241sAF10"><ref>#</ref><p>
The Hebrew UniversityHadassah Medical School.</p></note></author><author xml:id="author-0010" role="corresp"><persName><surname>Porgador</surname><forename type="first">Angel</forename></persName><note place="foot" n="bi051241sAF4"><ref>§</ref><p>
Ben Gurion University of the Negev.</p></note><affiliation role="corresp"> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</affiliation></author><idno type="istex">5FAA5D798F3882D8996FDF98C2E4917BAC44185C</idno><idno type="ark">ark:/67375/TPS-XC1SB6GX-4</idno><idno type="DOI">10.1021/bi051241s</idno></analytic><monogr><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="acspubs">bi</idno><idno type="coden">bichaw</idno><idno type="pISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2005</date><date type="published">2005</date><biblScope unit="vol">44</biblScope><biblScope unit="issue">44</biblScope><biblScope unit="page" from="14477">14477</biblScope><biblScope unit="page" to="14485">14485</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.41" when="2020-04-06"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p><graphic url="bi051241sn00001.tif"></graphic></p><p>NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors
(NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of
tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan
sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells
by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in
heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison
to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic
amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate.
Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity
but reduced its binding to tumor cells with a 10−100 fold lower <hi rend="italic">K</hi><hi rend="subscript">D</hi> when tested for direct binding to
heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight
saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively
monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and
N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in
NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and
cancers.
</p></abstract><textClass ana="subject"><keywords scheme="document-type-name"><term>Article</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2020-04-06" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI></fulltext><metadata><istex:metadataXml wicri:clean="corpus acs not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:document><article article-type="research-article" specific-use="acs2jats-2.0.3"><front><journal-meta><journal-id journal-id-type="acspubs">bi</journal-id><journal-id journal-id-type="coden">bichaw</journal-id><journal-title-group><journal-title>Biochemistry</journal-title><abbrev-journal-title>Biochemistry</abbrev-journal-title></journal-title-group><issn pub-type="ppub">0006-2960</issn><issn pub-type="epub">1520-4995</issn><publisher><publisher-name>American Chemical Society</publisher-name></publisher><self-uri>pubs.acs.org/biochemistry</self-uri></journal-meta><article-meta><article-id pub-id-type="doi">10.1021/bi051241s</article-id><article-categories><subj-group subj-group-type="document-type-name"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural
Cytotoxicity Receptor NKp46<xref rid="bi051241sAF2">†</xref></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zilka</surname><given-names>Alon</given-names></name><xref rid="bi051241sAF3">‡</xref><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Landau</surname><given-names>Guy</given-names></name><xref rid="bi051241sAF3">‡</xref><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Hershkovitz</surname><given-names>Oren</given-names></name><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Bloushtain</surname><given-names>Noga</given-names></name><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Bar-Ilan</surname><given-names>Ahuva</given-names></name><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Benchetrit</surname><given-names>Fabrice</given-names></name><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>Fima</surname><given-names>Eyal</given-names></name><xref rid="bi051241sAF4">§</xref></contrib><contrib contrib-type="author"><name><surname>van Kuppevelt</surname><given-names>Toin H.</given-names></name><xref rid="bi051241sAF5">‖</xref></contrib><contrib contrib-type="author"><name><surname>Gallagher</surname><given-names>John T.</given-names></name><xref rid="bi051241sAF6">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Elgavish</surname><given-names>Sharona</given-names></name><xref rid="bi051241sAF10">#</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Porgador</surname><given-names>Angel</given-names></name><xref rid="bi051241sAF1">*</xref><xref rid="bi051241sAF4">§</xref></contrib><aff>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion University
of the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, The
Netherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,
Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,
Jerusalem 91120, Israel
</aff></contrib-group><author-notes><fn id="bi051241sAF3"><label>‡</label><p>
A.Z. and G.L. contributed equally to this work.</p></fn><fn id="bi051241sAF4"><label>§</label><p>
Ben Gurion University of the Negev.</p></fn><fn id="bi051241sAF5"><label>‖</label><p>
University Medical Center.</p></fn><fn id="bi051241sAF6"><label>⊥</label><p>
University of Manchester.</p></fn><fn id="bi051241sAF10"><label>#</label><p>
The Hebrew UniversityHadassah Medical School.</p></fn><corresp id="bi051241sAF1">
To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</corresp></author-notes><pub-date pub-type="epub"><day>14</day><month>10</month><year>2005</year></pub-date><pub-date pub-type="ppub"><day>08</day><month>11</month><year>2005</year></pub-date><volume>44</volume><issue>44</issue><fpage>14477</fpage><lpage>14485</lpage><history><date date-type="received"><day>28</day><month>06</month><year>2005</year></date><date date-type="rev-recd"><day>04</day><month>09</month><year>2005</year></date><date date-type="asap"><day>14</day><month>10</month><year>2005</year></date><date date-type="issue-pub"><day>08</day><month>11</month><year>2005</year></date></history><permissions><copyright-statement>Copyright © 2005 American Chemical Society</copyright-statement><copyright-year>2005</copyright-year><copyright-holder>American Chemical Society</copyright-holder></permissions><abstract><graphic content-type="abstract-graphic" xlink:href="bi051241sn00001.tif"></graphic><p>NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors
(NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of
tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan
sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells
by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in
heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison
to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic
amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate.
Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity
but reduced its binding to tumor cells with a 10−100 fold lower <italic>K</italic><sub>D</sub> when tested for direct binding to
heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight
saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively
monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and
N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in
NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and
cancers.
</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>bi051241s</meta-value></custom-meta></custom-meta-group></article-meta><notes id="bi051241sAF2"><label>†</label><p>
This study was supported by grants from the Prostate Cancer
Foundation Israel, the Cancer Research Institute (CRI), and the Israel
Cancer Research Foundation (ICRF). This work was also supported
by the Cooperation Program in Cancer Research of the Deutsches
Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science
(MOS).</p></notes></front><body></body><back></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†</title></titleInfo><titleInfo contentType="CDATA"><title>Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†</title></titleInfo><name type="personal"><namePart type="family">ZILKA</namePart><namePart type="given">Alon</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> A.Z. and G.L. contributed equally to this work.</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">LANDAU</namePart><namePart type="given">Guy</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> A.Z. and G.L. contributed equally to this work.</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">HERSHKOVITZ</namePart><namePart type="given">Oren</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">BLOUSHTAIN</namePart><namePart type="given">Noga</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">BAR-ILAN</namePart><namePart type="given">Ahuva</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">BENCHETRIT</namePart><namePart type="given">Fabrice</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">FIMA</namePart><namePart type="given">Eyal</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">VAN KUPPEVELT</namePart><namePart type="given">Toin H.</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> University Medical Center.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">GALLAGHER</namePart><namePart type="given">John T.</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> University of Manchester.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="family">ELGAVISH</namePart><namePart type="given">Sharona</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> The Hebrew UniversityHadassah Medical School.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="family">PORGADOR</namePart><namePart type="given">Angel</namePart><affiliation>Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion Universityof the Negev, Beer Sheva 84105, Israel, Department of Biochemistry, University Medical Center, NCMLS, Nijmegen, TheNetherlands, Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust,Manchester M204BX, United Kingdom, and The Bioinformatics Unit, The Hebrew UniversityHadassah Medical School,Jerusalem 91120, Israel</affiliation><affiliation> Ben Gurion University of the Negev.</affiliation><affiliation> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>American Chemical Society</publisher><dateCreated encoding="w3cdtf">2005-10-14</dateCreated><dateIssued encoding="w3cdtf">2005-11-08</dateIssued><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><note type="footnote" ID="bi051241sAF2"> This study was supported by grants from the Prostate Cancer Foundation Israel, the Cancer Research Institute (CRI), and the Israel Cancer Research Foundation (ICRF). This work was also supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science (MOS).</note><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract>NKp46 is a member of a group of receptors collectively termed natural cytotoxicity receptors (NCRs) that are expressed by natural killer (NK) cells. NCRs are capable of mediating direct killing of tumor and virus-infected cells by NK cells. We have recently shown that NKp46 recognizes the heparan sulfate moieties of membranal heparan sulfate proteoglycans (HSPGs), thus enabling lysis of tumor cells by NK cells. In the current study, we further examined the residues in NKp46 that may be involved in heparan sulfate binding on tumor cells. On the basis of both the electrostatic potential map and comparison to the heparin binding site on human fibronectin, we predicted a continuous region containing the basic amino acids K133, R136, H139, R142, and K146 to be involved in NKp46 binding to heparan sulfate. Mutating these amino acids on NKp46D2 to noncharged amino acids retained its virus binding capacity but reduced its binding to tumor cells with a 10−100 fold lower KD when tested for direct binding to heparin. The minimal length of the heparin/heparan sulfate epitope recognized by NKp46 was eight saccharides as predicted from the structure and proven by testing heparin oligomers. Testing selectively monodesulfated heparin oligomers emphasized the specific contributions of O-sulfation, N-sulfation, and N-acetylation to epitope recognition by NKp46. The characterization of heparan sulfate binding region in NKp46 offers further insight into the identity of the ligands for NKp46 and the interaction of NK and cancers.</abstract><note type="footnote" ID="bi051241sAF2"> This study was supported by grants from the Prostate Cancer Foundation Israel, the Cancer Research Institute (CRI), and the Israel Cancer Research Foundation (ICRF). This work was also supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science (MOS).</note><relatedItem type="host"><titleInfo><title>Biochemistry</title></titleInfo><titleInfo type="abbreviated"><title>Biochemistry</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0006-2960</identifier><identifier type="eISSN">1520-4995</identifier><identifier type="acspubs">bi</identifier><identifier type="coden">BICHAW</identifier><identifier type="uri">pubs.acs.org/biochemistry</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>44</number></detail><detail type="issue"><caption>no.</caption><number>44</number></detail><extent unit="pages"><start>14477</start><end>14485</end></extent></part></relatedItem><identifier type="istex">5FAA5D798F3882D8996FDF98C2E4917BAC44185C</identifier><identifier type="ark">ark:/67375/TPS-XC1SB6GX-4</identifier><identifier type="DOI">10.1021/bi051241s</identifier><accessCondition type="use and reproduction" contentType="restricted">Copyright © 2005 American Chemical Society</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-X5HBJWF8-J">acs</recordContentSource><recordOrigin>Converted from (version 1.2.10) to MODS version 3.6.</recordOrigin><recordCreationDate encoding="w3cdtf">2020-04-10</recordCreationDate></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/record.json</uri></json:item></metadata><annexes><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/5FAA5D798F3882D8996FDF98C2E4917BAC44185C/annexes/tiff</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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