Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†
Identifieur interne : 000871 ( Istex/Curation ); précédent : 000870; suivant : 000872Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†
Auteurs : Alon Zilka [Israël] ; Guy Landau [Israël] ; Oren Hershkovitz [Israël] ; Noga Bloushtain [Israël] ; Ahuva Bar-Ilan [Israël] ; Fabrice Benchetrit [Israël] ; Eyal Fima [Israël] ; Toin H. Van Kuppevelt [Israël] ; John T. Gallagher [Israël] ; Sharona Elgavish [Israël] ; Angel Porgador [Israël]Source :
- 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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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</wicri:regionArea></affiliation><affiliation><mods:affiliation> A.Z. and G.L. contributed equally to this work.</mods:affiliation><wicri:noCountry code="no comma"> A.Z. and G.L. contributed equally to this work.</wicri:noCountry></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></affiliation></author><author><name sortKey="Landau, Guy" sort="Landau, Guy" uniqKey="Landau G" first="Guy" last="Landau">Guy Landau</name><affiliation wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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 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Negev.</wicri:noCountry></affiliation></author><author><name sortKey="Bloushtain, Noga" sort="Bloushtain, Noga" uniqKey="Bloushtain N" first="Noga" last="Bloushtain">Noga Bloushtain</name><affiliation wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></affiliation></author><author><name sortKey="Benchetrit, 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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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></affiliation></author><author><name sortKey="Fima, Eyal" sort="Fima, Eyal" uniqKey="Fima E" first="Eyal" last="Fima">Eyal Fima</name><affiliation wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> University Medical Center.</mods:affiliation><wicri:noCountry code="no comma"> University Medical Center.</wicri:noCountry></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> University of Manchester.</mods:affiliation><wicri:noCountry code="no comma"> University of Manchester.</wicri:noCountry></affiliation></author><author><name sortKey="Elgavish, Sharona" sort="Elgavish, Sharona" uniqKey="Elgavish S" first="Sharona" last="Elgavish">Sharona Elgavish</name><affiliation wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> The Hebrew UniversityHadassah Medical School.</mods:affiliation><wicri:noCountry code="no comma"> The Hebrew UniversityHadassah Medical School.</wicri:noCountry></affiliation></author><author><name sortKey="Porgador, Angel" sort="Porgador, Angel" uniqKey="Porgador A" first="Angel" last="Porgador">Angel Porgador</name><affiliation wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation><wicri:noCountry code="no comma"> Ben Gurion University of the Negev.</wicri:noCountry></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</mods:affiliation><country wicri:rule="url">Israël</country></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><idno type="wicri:Area/Istex/Curation">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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></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 wicri:level="1"><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><country xml:lang="fr">Israël</country><wicri:regionArea>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</wicri:regionArea></affiliation><affiliation><mods:affiliation> Ben Gurion University of the Negev.</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Telephone: (972)-86477283. Fax: (972)-86477626. E-mail: angel@bgu.ac.il.</mods:affiliation><country wicri:rule="url">Israël</country></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></record>Pour manipuler ce document sous Unix (Dilib)
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|texte= Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†
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