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    Characterization of the heparin/heparan sulfate binding site of the natural cytotoxicity receptor NKp46.

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    Authors
    Zilka, Alon
    Landau, Guy
    Hershkovitz, Oren
    Bloushtain, Noga
    Bar-Ilan, Ahuva
    Benchetrit, Fabrice
    Fima, Eyal
    Van Kuppevelt, Toin H
    Gallagher, John T
    Elgavish, Sharona
    Porgador, Angel
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    Affiliation
    Department of Microbiology and Immunology, Faculty of Health Sciences, and Cancer Research Center, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
    Issue Date
    2005-11-08
    
    Metadata
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    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 K(D) 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.
    Citation
    Characterization of the heparin/heparan sulfate binding site of the natural cytotoxicity receptor NKp46. 2005, 44 (44):14477-85 Biochemistry
    Journal
    Biochemistry
    URI
    http://hdl.handle.net/10541/76274
    DOI
    10.1021/bi051241s
    PubMed ID
    16262248
    Type
    Article
    Language
    en
    ISSN
    0006-2960
    ae974a485f413a2113503eed53cd6c53
    10.1021/bi051241s
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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