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J Biol Chem, Vol. 275, Issue 3, 2165-2173, January 21, 2000

Determinants of the Peptide-induced Conformational Change in the Human Class II Major Histocompatibility Complex Protein HLA-DR1*

Aaron K. SatoDagger §, Jennifer A. ZarutskieDagger §, Mia M. Rushe, Aleksey Lomakin, Sateesh K. Natarajanpar , Scheherazade Sadegh-Nasseripar , George B. Benedek, and Lawrence J. SternDagger **

From the Departments of Dagger  Chemistry and  Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and the par  Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The human class II major histocompatibility complex protein HLA-DR1 has been shown previously to undergo a distinct conformational change from an open to a compact form upon binding peptide. To investigate the role of peptide in triggering the conformational change, the minimal requirements for inducing the compact conformation were determined. Peptides as short as two and four residues, which occupy only a small fraction of the peptide-binding cleft, were able to induce the conformational change. A mutant HLA-DR1 protein with a substitution in the beta  subunit designed to fill the P1 pocket from within the protein (Gly86 to Tyr) adopted to a large extent the compact, peptide-bound conformation. Interactions important in stabilizing the compact conformation are shown to be distinct from those responsible for high affinity binding or for stabilization of the complex against thermal denaturation. The results suggest that occupancy of the P1 pocket is responsible for partial conversion to the compact form but that both side chain and main chain interactions contribute to the full conformational change. The implications of the conformational change to intracellular antigen loading and presentation are discussed.

* This work was supported by National Institutes of Health Grants R01-AI38996 (to L. J. S.), P01-GM56552 (to L. J. S.), and R01-GM53549 (to S. S. N.), Council for Tobacco Research Grant 4314 (to S. S. N.), and a Merck predoctoral fellowship (to J. A. Z).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.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed: Dept. of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139. E-mail: stern@mit.edu.

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