The MHC Class I heavy chain structurally conserved cysteines 101 and 164 participate in HLA-B27 dimer formation

Antioxid Redox Signal. 2012 Jan 1;16(1):33-43. doi: 10.1089/ars.2010.3693. Epub 2011 Sep 15.

Abstract

Aims: The human leukocyte antigen (HLA)-B27 is strongly associated with a group of inflammatory arthritic disorders known as the spondyloarthropathies (SpAs). The unusual biochemistry of HLA-B27 has been proposed to participate in disease development, especially the enhanced ability of HLA-B27 to form several heavy chain-dimer populations. HLA-B27 possesses three unpaired cysteine (C) residues at position 67, 308, and 325, in addition to the four conserved cysteine residues at p101, 164, 203, and 259. C67 was proposed to participate in dimer formation of recombinant HLA-B27 protein and in vivo heavy chain-dimers. However, the structurally conserved C164 was demonstrated to participate in endoplasmic reticulum (ER) resident heavy chain-dimer formation. We therefore wanted to determine whether these aggregates involve cysteines other than C164 and the basis for the difference between the observed heavy chain-dimer species.

Results: We determined that C164 and C101 can form distinct dimer structures and that the heterogenous nature of heavy chain-dimer species is due to differences in both redox status and conformation. Different HLA-B27 dimer populations can be found in physiologically relevant cell types derived from HLA-B27-positive patients with inflammatory arthritis. In addition, HLA-B27 dimer formation can be correlated with cellular stress induction.

Innovation: The use of both mutagenesis and manipulating cellular redox environments demonstrates that HLA-B27 dimerization requires both specific cysteine?cysteine interactions and conformations with differing redox states.

Conclusion: HLA-B27 heavy chain-dimerization is a complex process and these findings provide an insight into HLA-B27 misfolding and a potential contribution to inflammatory disease development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Conserved Sequence
  • Cysteine / genetics
  • Cysteine / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • HLA-B27 Antigen / chemistry*
  • HLA-B27 Antigen / genetics
  • HLA-B27 Antigen / metabolism
  • Humans
  • Molecular Weight
  • Oxidation-Reduction
  • Protein Multimerization / physiology
  • Rats

Substances

  • Activating Transcription Factor 6
  • HLA-B27 Antigen
  • Cysteine