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 Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doebele, R. C. Articles by Mellins, E. D. Search for Related Content PubMed PubMed Citation Articles by Doebele, R. C. Articles by Mellins, E. D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE

Point Mutations in or Near the Antigen-Binding Groove of HLA-DR3 Implicate Class II-Associated Invariant Chain Peptide Affinity as a Constraint on MHC Class II Polymorphism¹

Robert C. Doebele^*, Achal Pashine^*, Wendy Liu^*, Dennis M. Zaller, Michael Belmares, Robert Busch^2,3,* and Elizabeth D. Mellins^3,4,*

^* Division of Immunology and Transplantation Biology, Department of Pediatrics, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, CA 94305; Merck Research Laboratories, Rahway, NJ 07065; and Department of Chemistry, Stanford University, Stanford, CA 94305

During maturation of MHC II molecules, newly synthesized and assembled complexes of MHC II dimers with invariant chain (Ii) are targeted to endosomes, where Ii is proteolyzed, leaving remnant class II-associated Ii peptides (CLIP) in the MHC II peptide binding groove. CLIP must be released, usually with assistance from the endosomal MHC II peptide exchange factor, HLA-DM, before MHC II molecules can bind endosomal peptides. Structural factors that control rates of CLIP release remain poorly understood, although peptide side chain-MHC II specificity pocket interactions and MHC II polymorphism are important. Here we report that mutations S11F, S13Y, Q70R, K71E, K71N, and R74Q, which map to the P4 and P6 pockets of the groove of HLA-DR3 molecules, as well as G20E adjacent to the groove, are associated with elevated CLIP in cells. Most of these mutations increase the resistance of CLIP-DR3 complexes to dissociation by SDS. In vitro, the groove mutations increase the stability of CLIP-DR3 complexes to dissociation. Dissociation rates in the presence of DM, as well as coimmunoprecipitation of some mutant DR3 molecules with DM, are also diminished. The profound phenotypes associated with some of these point mutations suggest that the need to maintain efficient CLIP release represents a constraint on naturally occurring MHC II polymorphism.

Related articles in The JI:

IN THIS ISSUE

The JI 2003 170: 4423-4424. [Full Text]  

This article has been cited by other articles:

				L.-E. Fallang, S. Roh, A. Holm, E. Bergseng, T. Yoon, B. Fleckenstein, A. Bandyopadhyay, E. D. Mellins, and L. M. Sollid Complexes of Two Cohorts of CLIP Peptides and HLA-DQ2 of the Autoimmune DR3-DQ2 Haplotype Are Poor Substrates for HLA-DM J. Immunol., October 15, 2008; 181(8): 5451 - 5461. [Abstract] [Full Text] [PDF]

				C. H. Rinderknecht, M. P. Belmares, T. L. W. Catanzarite, A. J. Bankovich, T. H. Holmes, K. C. Garcia, N. K. Nanda, R. Busch, S. Kovats, and E. D. Mellins Posttranslational Regulation of I-Ed by Affinity for CLIP J. Immunol., November 1, 2007; 179(9): 5907 - 5915. [Abstract] [Full Text] [PDF]

				J. E. Collins, J. M. Heward, J. M. M. Howson, H. Foxall, J. Carr-Smith, J. A. Franklyn, and S. C. L. Gough Common Allelic Variants of Exons 10, 12, and 33 of the Thyroglobulin Gene Are Not Associated with Autoimmune Thyroid Disease in the United Kingdom J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6336 - 6339. [Abstract] [Full Text] [PDF]