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-Chain1
* Departments of Pathology, and Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655; and
Department of Molecular, Cellular, and Developmental Biology, Harvard University, Cambridge, MA 02138
The class II MHC homolog HLA-DM catalyzes exchange of peptides
bound to class II MHC proteins, and is an important component of the Ag
presentation machinery. The mechanism of HLA-DM-mediated catalysis is
largely obscure. HLA-DM catalyzes exchange of peptides of varying
sequence, suggesting that a peptide sequence-independent component of
the MHC-peptide interaction could be involved in the catalytic process.
Twelve conserved hydrogen bonds between the peptide backbone and the
MHC are a prominent sequence-independent feature of the MHC-peptide
interaction. To evaluate the relative importance of these hydrogen
bonds toward HLA-DM action, we prepared peptide variants that lacked
the ability to form one or more of the hydrogen bonds as a result of
backbone amide N-methylation or truncation, and tested
their ability to be exchanged by HLA-DM. We found that disruption of
hydrogen bonds involving HLA-DR1 residues 
51–53, a short extended
segment at the N terminus of the subunit helical region, led to
heightened HLA-DM catalytic efficacy. We propose that those bonds are
disrupted in the MHC conformation recognized by HLA-DM to allow
structural transitions in that area during DM-assisted peptide release.
These results suggest that peptides or compounds that bind MHC but
cannot form these interactions would be preferentially edited out by
HLA-DM.
This article has been cited by other articles:
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  Z. Zhou, K. A. Callaway, D. A. Weber, and P. E. Jensen Cutting Edge: HLA-DM Functions through a Mechanism That Does Not Require Specific Conserved Hydrogen Bonds in Class II MHC-Peptide Complexes J. Immunol., October 1, 2009; 183(7): 4187 - 4191. [Abstract] [Full Text] [PDF]
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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]
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 C. A. Lazarski, F. A. Chaves, and A. J. Sant The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability J. Exp. Med., May 15, 2006; 203(5): 1319 - 1328. [Abstract] [Full Text] [PDF]
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S. B. Lovitch, Z. Pu, and E. R. Unanue Amino-Terminal Flanking Residues Determine the Conformation of a Peptide-Class II MHC Complex. J. Immunol., March 1, 2006; 176(5): 2958 - 2968. [Abstract] [Full Text] [PDF]
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 E. Bergseng, J. Xia, C.-Y. Kim, C. Khosla, and L. M. Sollid Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule J. Biol. Chem., June 10, 2005; 280(23): 21791 - 21796. [Abstract] [Full Text] [PDF]
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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]
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