5ksv | pdb_00005ksv
Crystal structure of HLA-DQ2.5-CLIP2
Structural highlights
Publication Abstract from PubMedHuman leukocyte antigen (HLA)-DQ2.5 (DQA1*05/DQB1*02) is a class-II major histocompatibility complex protein associated with both type 1 diabetes and celiac disease. One unusual feature of DQ2.5 is its high class-II-associated invariant chain peptide (CLIP) content. Moreover, HLA-DQ2.5 preferentially binds the non-canonical CLIP2 over the canonical CLIP1. To better understand the structural basis of HLA-DQ2.5's unusual CLIP association characteristics, better insight into the HLA-DQ2.5.CLIP complex structures is required. To this end, we determined the X-ray crystal structure of the HLA-DQ2.5. CLIP1 and HLA-DQ2.5.CLIP2 complexes at 2.73 and 2.20 A, respectively. We found that HLA-DQ2.5 has an unusually large P4 pocket and a positively charged peptide-binding groove that together promote preferential binding of CLIP2 over CLIP1. An alpha9-alpha22-alpha24-alpha31-beta86-beta90 hydrogen bond network located at the bottom of the peptide-binding groove, spanning from the P1 to P4 pockets, renders the residues in this region relatively immobile. This hydrogen bond network, along with a deletion mutation at alpha53, may lead to HLA-DM insensitivity in HLA-DQ2.5. A molecular dynamics simulation experiment reported here and recent biochemical studies by others support this hypothesis. The diminished HLA-DM sensitivity is the likely reason for the CLIP-rich phenotype of HLA-DQ2.5. Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-associated invariant chain peptides.,Nguyen TB, Jayaraman P, Bergseng E, Madhusudhan MS, Kim CY, Sollid LM J Biol Chem. 2017 Jun 2;292(22):9218-9228. doi: 10.1074/jbc.M117.785139. Epub, 2017 Mar 31. PMID:28364043[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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