MersV1, Main, Exploration, bibRecord, 002F44

Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†

Identifieur interne : 002F44 ( Main/Exploration ); précédent : 002F43; suivant : 002F45

Characterization 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.

RBID : ISTEX:5FAA5D798F3882D8996FDF98C2E4917BAC44185C

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.

Url:

https://api.istex.fr/ark:/67375/TPS-XC1SB6GX-4/fulltext.pdf

DOI: 10.1021/bi051241s

Affiliations:

Israël

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<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>
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Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†

Characterization of the Heparin/Heparan Sulfate Binding Site of the Natural Cytotoxicity Receptor NKp46†

Source :

Abstract

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Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

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