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*
Department of Pediatrics, Stanford University Medical Center, Stanford, CA 94305;
School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Pediatric Rheumatology, University of California at San Francisco Medical Center, San Francisco, CA 94143.
HLA-DM (abbreviated DM) is an MHC-encoded glycoprotein that
catalyzes the selective release of peptides, including class
II-associated invariant chain peptides, from MHC class II molecules. To
perform its function, DM must assemble in the endoplasmic reticulum
(ER), travel to endosomes, and interact productively with class II
molecules. We have described previously an EBV-transformed B cell line,
7.12.6, which displays a partial Ag presentation defect and expresses a
mutated DM ß-chain with Cys79 replaced by Tyr. In this study, we show
that HLA-DR molecules in 7.12.6 have a defect in peptide loading and
accumulate class II-associated invariant chain peptides (CLIP). Peptide
loading is restored by transfection of wild-type DMB. The mutant DM
molecules exit the ER slowly and are degraded rapidly, resulting in
greatly reduced levels of mutant DM in post-Golgi compartments. Whereas
wild-type DM forms noncovalent 
ß dimers, such dimers form
inefficiently in 7.12.6; many mutant DM ß-chains instead form a
disulfide-bonded dimer with DM . Homodimers of DM ß are also
detected in 7.12.6 and in the -chain defective mutant, 2.2.93. We
conclude that during folding of wild-type DM, the native conformation
is stabilized by a conserved disulfide bond involving Cys79ß and by
noncovalent contacts with DM . Without these interactions, DM ß
can form malfolded structures containing interchain disulfide bonds;
malfolding is correlated with ER retention and accelerated degradation.
This article has been cited by other articles:
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A. W. Lee, L. Hertel, R. K. Louie, T. Burster, V. Lacaille, A. Pashine, D. A. Abate, E. S. Mocarski, and E. D. Mellins Human Cytomegalovirus Alters Localization of MHC Class II and Dendrite Morphology in Mature Langerhans Cells J. Immunol., September 15, 2006; 177(6): 3960 - 3971. [Abstract] [Full Text] [PDF]
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R. C. Doebele, A. Pashine, W. Liu, D. M. Zaller, M. Belmares, R. Busch, and E. D. Mellins 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 Polymorphism J. Immunol., May 1, 2003; 170(9): 4683 - 4692. [Abstract] [Full Text] [PDF]
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M. P. Belmares, R. Busch, K. W. Wucherpfennig, H. M. McConnell, and E. D. Mellins Structural Factors Contributing to DM Susceptibility of MHC Class II/Peptide Complexes J. Immunol., November 1, 2002; 169(9): 5109 - 5117. [Abstract] [Full Text] [PDF]
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N. S. Patil, A. Pashine, M. P. Belmares, W. Liu, B. Kaneshiro, J. Rabinowitz, H. McConnell, and E. D. Mellins Rheumatoid Arthritis (RA)-Associated HLA-DR Alleles Form Less Stable Complexes with Class II-Associated Invariant Chain Peptide Than Non-RA-Associated HLA-DR Alleles J. Immunol., December 15, 2001; 167(12): 7157 - 7168. [Abstract] [Full Text] [PDF]
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 R. Busch, Z. Reich, D. M. Zaller, V. Sloan, and E. D. Mellins Secondary Structure Composition and pH-dependent Conformational Changes of Soluble Recombinant HLA-DM J. Biol. Chem., October 16, 1998; 273(42): 27557 - 27564. [Abstract] [Full Text] [PDF]
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C. B. Guerra, R. Busch, R. C. Doebele, W. Liu, T. Sawada, W. W. Kwok, M.-d. Y. Chang, and E. D. Mellins Novel Glycosylation of HLA-DR{alpha} Disrupts Antigen Presentation Without Altering Endosomal Localization J. Immunol., May 1, 1998; 160(9): 4289 - 4297. [Abstract] [Full Text] [PDF]
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