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J Biol Chem, Vol. 275, Issue 8, 5472-5477, February 25, 2000

Identification of the Peptide-binding Site in the Heat Shock Chaperone/Tumor Rejection Antigen gp96 (Grp94)*

Nora A. LinderothDagger , Anthony Popowicz§, and Srin SastryDagger

From the Dagger  Laboratory of Molecular Genetics, Box 174, and § Computing Services, The Rockefeller University, New York, New York 10021

Heat shock protein (HSP)-peptide complexes from tumor cells elicit specific protective immunity when injected into inbred mice bearing the same specific type of tumor. The HSP-mediated specific immunogenicity also occurs with virus-infected cells. The immune response is solely due to endogenous peptides noncovalently bound to HSP. A vesicular stomatitis virus capsid-derived peptide ligand bearing a photoreactive azido group was specifically bound by and cross-linked to murine HSP glycoprotein (gp) 96. The peptide-binding site was mapped by specific proteolysis of the cross-links followed by analysis of the cross-linked peptides using a judicious combination of SDS-gel electrophoresis, mass spectrometry, and amino acid sequencing. The minimal peptide-binding site was mapped to amino acid residues 624-630 in a highly conserved region of gp96. A model of the peptide binding pocket of gp96 was constructed based on the known crystallographic structure of major histocompatibility complex class I molecule bound to a similar peptide. The gp96-peptide model predicts that the peptide ligand is held in a groove formed by alpha -helices and lies on a surface consisting of antiparallel beta -sheets. Interestingly, in this model, the peptide binding pocket abuts the dimerization domain of gp96, which may have implications for the extraordinary stability of peptide-gp96 complexes, and for the faithful relay of peptides to major histocompatibility complex class I molecule for antigen presentation.

* This work was supported by a research grant from Antigenics L.L.C. New York.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Molecular Genetics Box 174, The Rockefeller University, 1230 York Ave., New York, NY 10021. Tel.: 212-327-8987; Fax: 212-327-8651; E-mail: sastrys@rockvax.rockefeller.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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