Conformational variation in structures of classical and non-classical MHCII proteins and functional implications

Authors

  • Corrie A. Painter,

    1. Department of Biochemistry and Molecular Pharmacology and Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
    Search for more papers by this author
  • Lawrence J. Stern

    Corresponding author
    • Department of Biochemistry and Molecular Pharmacology and Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
    Search for more papers by this author

Correspondence to:

Lawrence J. Stern

S2-127 UMass Medical School

55 Lake Avenue North

Worcester, MA 01655, USA

Tel.: +1 508 856 1931

Fax: +1 508 856 0019

e-mail: lawrence.stern@umassmed.edu

Summary

Recent structural characterizations of classical and non-classical major histocompatibility complex class II (MHCII) proteins have provided a view into the dynamic nature of the MHCII–peptide binding groove and the role that structural changes play in peptide loading processes. Although there have been numerous reports of crystal structures for MHCII–peptide complexes, a detailed analysis comparing all the structures has not been reported, and subtle conformational variations present in these structures may not have been fully appreciated. We compared the 91 MHCII crystal structures reported in the PDB to date, including an HLA-DR mutant particularly susceptible to DM-mediated peptide exchange, and reviewed experimental and computational studies of the effect of peptide binding on MHCII structure. These studies provide evidence for conformational lability in and around the α-subunit 3-10 helix at residues α48-51, a region known to be critical for HLA-DM-mediated peptide exchange. A biophysical study of MHC–peptide hydrogen bond strengths and a recent structure of the non-classical MHCII protein HLA-DO reveal changes in the same region. Conformational variability was observed also in the vicinity of a kink in the β-subunit helical region near residue β66 and in the orientation and loop conformation in the β2 Ig domain. Here, we provide an overview of the regions within classical and non-classical MHCII proteins that display conformational changes and the potential role that these changes may have in the peptide loading/exchange process.

Ancillary