HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Natarajan, S. K. Articles by Sadegh-Nasseri, S. Search for Related Content PubMed PubMed Citation Articles by Natarajan, S. K. Articles by Sadegh-Nasseri, S.

Stable Peptide Binding to MHC Class II Molecule Is Rapid and Is Determined by a Receptive Conformation Shaped by Prior Association with Low Affinity Peptides¹

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Formation of stable class II MHC/peptide complex involves conformational changes and proceeds via an intermediate. Although this intermediate complex forms and dissociates in minutes, its conversion to a stable complex is a very slow process, taking up to a few days to reach completion. Here, we investigate the different steps of this binding and demonstrate that the conformational changes necessary to generate a receptive molecule is the rate-determining slow step in the process, while formation of the stable MHC/peptide complex is very rapid. With HLA-DR1 as our model class II molecule, we first used low affinity variants of hemagglutinin peptide (HA_306–318), which lack the principal anchor, to shape the conformation of the MHC and then studied the kinetics of stable binding of HA_306–318 to such an induced conformation. We found that the apparent association rate of HA_306–318 is equivalent to the dissociation rate of the low affinity peptide. A 4- to 18-fold enhancement in the binding rates of HA_306–318 was observed depending on the dissociation rates of the low affinity peptides. These results establish that 1) formation of stable MHC/peptide complexes is very rapid and 2) prior binding of low affinity peptide induces a receptive conformation in MHC for efficient stable peptide binding. Furthermore, in the absence of any free peptide, this receptive molecule rapidly reverts to slow binding behavior toward the subsequently offered peptide. These results have important implications for the roles of low affinity MHC/peptide complexes in Ag presentation.

This article has been cited by other articles:

				M. J. Call, X. Xing, G. D. Cuny, N. P. Seth, D. M. Altmann, L. Fugger, M. Krogsgaard, R. L. Stein, and K. W. Wucherpfennig In Vivo Enhancement of Peptide Display by MHC Class II Molecules with Small Molecule Catalysts of Peptide Exchange J. Immunol., May 15, 2009; 182(10): 6342 - 6352. [Abstract] [Full Text] [PDF]

				I. Potolicchio, S. Chitta, X. Xu, D. Fonseca, G. Crisi, V. Horejsi, J. L. Strominger, L. J. Stern, G. Raposo, and L. Santambrogio Conformational Variation of Surface Class II MHC Proteins during Myeloid Dendritic Cell Differentiation Accompanies Structural Changes in Lysosomal MIIC J. Immunol., October 15, 2005; 175(8): 4935 - 4947. [Abstract] [Full Text] [PDF]

				V. Marin-Esteban, K. Falk, and O. Rotzschke "Chemical Analogues" of HLA-DM Can Induce a Peptide-receptive State in HLA-DR Molecules J. Biol. Chem., December 3, 2004; 279(49): 50684 - 50690. [Abstract] [Full Text] [PDF]

				S. Mirshahidi, L. C. K. Ferris, and S. Sadegh-Nasseri The Magnitude of TCR Engagement Is a Critical Predictor of T Cell Anergy or Activation J. Immunol., May 1, 2004; 172(9): 5346 - 5355. [Abstract] [Full Text] [PDF]

				G. J. Carven, S. Chitta, I. Hilgert, M. M. Rushe, R. F. Baggio, M. Palmer, J. E. Arenas, J. L. Strominger, V. Horejsi, L. Santambrogio, et al. Monoclonal Antibodies Specific for the Empty Conformation of HLA-DR1 Reveal Aspects of the Conformational Change Associated with Peptide Binding J. Biol. Chem., April 16, 2004; 279(16): 16561 - 16570. [Abstract] [Full Text] [PDF]

				J. C. Huang, M. Han, A. Minguela, S. Pastor, A. Qadri, and E. S. Ward T Cell Recognition of Distinct Peptide:I-Au Conformers in Murine Experimental Autoimmune Encephalomyelitis J. Immunol., September 1, 2003; 171(5): 2467 - 2477. [Abstract] [Full Text] [PDF]

				C. H. Koonce, G. Wutz, E. J. Robertson, A. B. Vogt, H. Kropshofer, and E. K. Bikoff DM Loss in k Haplotype Mice Reveals Isotype-Specific Chaperone Requirements J. Immunol., April 1, 2003; 170(7): 3751 - 3761. [Abstract] [Full Text] [PDF]

				S. Mirshahidi, C.-T. Huang, and S. Sadegh-Nasseri Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor J. Exp. Med., September 17, 2001; 194(6): 719 - 732. [Abstract] [Full Text] [PDF]

				P. J. Chefalo and C. V. Harding Processing of Exogenous Antigens for Presentation by Class I MHC Molecules Involves Post-Golgi Peptide Exchange Influenced by Peptide-MHC Complex Stability and Acidic pH J. Immunol., August 1, 2001; 167(3): 1274 - 1282. [Abstract] [Full Text] [PDF]

				J. F. Vacchino and H. M. McConnell Peptide Binding to Active Class II MHC Protein on the Cell Surface J. Immunol., June 1, 2001; 166(11): 6680 - 6685. [Abstract] [Full Text] [PDF]

				E. K. Bikoff, G. Wutz, G. A. Kenty, C. H. Koonce, and E. J. Robertson Relaxed DM Requirements During Class II Peptide Loading and CD4+ T Cell Maturation in BALB/c Mice J. Immunol., April 15, 2001; 166(8): 5087 - 5098. [Abstract] [Full Text] [PDF]

				C.-L. Chou and S. Sadegh-Nasseri Hla-Dm Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II J. Exp. Med., December 18, 2000; 192(12): 1697 - 1706. [Abstract] [Full Text] [PDF]

				C. Carstens, D. K. Newman, H. Bohlen, A. Konig, and N. Koch Invariant chains with the class II binding site replaced by a sequence from influenza virus matrix protein constrain low-affinity sequences to MHC II presentation Int. Immunol., November 1, 2000; 12(11): 1561 - 1568. [Abstract] [Full Text] [PDF]

				F. Micheletti, A. Canella, S. Vertuani, M. Marastoni, L. Tosi, S. Volinia, S. Traniello, and R. Gavioli Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses J. Immunol., October 15, 2000; 165(8): 4264 - 4271. [Abstract] [Full Text] [PDF]

				A. K. Sato, J. A. Zarutskie, M. M. Rushe, A. Lomakin, S. K. Natarajan, S. Sadegh-Nasseri, G. B. Benedek, and L. J. Stern Determinants of the Peptide-induced Conformational Change in the Human Class II Major Histocompatibility Complex Protein HLA-DR1 J. Biol. Chem., January 21, 2000; 275(3): 2165 - 2173. [Abstract] [Full Text] [PDF]

				E. Carrasco-Marin, S. Petzold, and E. R. Unanue Two Structural States of Complexes of Peptide and Class II Major Histocompatibility Complex Revealed by Photoaffinity-labeled Peptides J. Biol. Chem., October 29, 1999; 274(44): 31333 - 31340. [Abstract] [Full Text] [PDF]

				O. Rotzschke, K. Falk, J. Mack, J. M. Lau, G. Jung, and J. L. Strominger Conformational variants of class II MHC/peptide complexes induced by N- and C-terminal extensions of minimal peptide epitopes PNAS, June 22, 1999; 96(13): 7445 - 7450. [Abstract] [Full Text] [PDF]

				K. Falk, J. M. Lau, L. Santambrogio, V. M. Esteban, F. Puentes, O. Rotzschke, and J. L. Strominger Ligand Exchange of Major Histocompatibility Complex Class II Proteins Is Triggered by H-bond Donor Groups of Small Molecules J. Biol. Chem., January 18, 2002; 277(4): 2709 - 2715. [Abstract] [Full Text] [PDF]

				S. Surman, T. D. Lockey, K. S. Slobod, B. Jones, J. M. Riberdy, S. W. White, P. C. Doherty, and J. L. Hurwitz Localization of CD4+ T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing PNAS, April 10, 2001; 98(8): 4587 - 4592. [Abstract] [Full Text] [PDF]

				J. A. Zarutskie, R. Busch, Z. Zavala-Ruiz, M. Rushe, E. D. Mellins, and L. J. Stern The kinetic basis of peptide exchange catalysis by HLA-DM PNAS, October 23, 2001; 98(22): 12450 - 12455. [Abstract] [Full Text] [PDF]