Structural highlights
Function
DMA_HUMAN Plays a critical role in catalyzing the release of class II-associated invariant chain peptide (CLIP) from newly synthesized MHC class II molecules and freeing the peptide binding site for acquisition of antigenic peptides. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO.[1] [2] [3]
Publication Abstract from PubMed
HLA-DR molecules bind microbial peptides in an endosomal compartment and present them on the cell surface for CD4 T cell surveillance. HLA-DM plays a critical role in the endosomal peptide selection process. The structure of the HLA-DM-HLA-DR complex shows major rearrangements of the HLA-DR peptide-binding groove. Flipping of a tryptophan away from the HLA-DR1 P1 pocket enables major conformational changes that position hydrophobic HLA-DR residues into the P1 pocket. These conformational changes accelerate peptide dissociation and stabilize the empty HLA-DR peptide-binding groove. Initially, incoming peptides have access to only part of the HLA-DR groove and need to compete with HLA-DR residues for access to the P2 site and the hydrophobic P1 pocket. This energetic barrier creates a rapid and stringent selection process for the highest-affinity binders. Insertion of peptide residues into the P2 and P1 sites reverses the conformational changes, terminating selection through DM dissociation.
Crystal Structure of the HLA-DM-HLA-DR1 Complex Defines Mechanisms for Rapid Peptide Selection.,Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, Pyrdol J, Wucherpfennig KW Cell. 2012 Dec 21;151(7):1557-68. doi: 10.1016/j.cell.2012.11.025. PMID:23260142[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Weber DA, Evavold BD, Jensen PE. Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM. Science. 1996 Oct 25;274(5287):618-20. PMID:8849454
- ↑ Mosyak L, Zaller DM, Wiley DC. The structure of HLA-DM, the peptide exchange catalyst that loads antigen onto class II MHC molecules during antigen presentation. Immunity. 1998 Sep;9(3):377-83. PMID:9768757
- ↑ Nicholson MJ, Moradi B, Seth NP, Xing X, Cuny GD, Stein RL, Wucherpfennig KW. Small molecules that enhance the catalytic efficiency of HLA-DM. J Immunol. 2006 Apr 1;176(7):4208-20. PMID:16547258
- ↑ Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, Pyrdol J, Wucherpfennig KW. Crystal Structure of the HLA-DM-HLA-DR1 Complex Defines Mechanisms for Rapid Peptide Selection. Cell. 2012 Dec 21;151(7):1557-68. doi: 10.1016/j.cell.2012.11.025. PMID:23260142 doi:http://dx.doi.org/10.1016/j.cell.2012.11.025
