Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-Associated invariant chain peptides

Abstract

Human 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 HLADQ2.5 '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 α9-α22-α24-α31-α86-α90 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 α53, 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.