HLA-B27 lacking associated beta2-microglobulin rearranges to auto-display or cross-display residues 169-181: a novel molecular mechanism for spondyloarthropathies.
Expression of the MHC class I allele, HLA-B27, is correlated with autoimmune disease. The misfolding and association of B27 heavy chains through non-native disulfide bonds has recently been implicated. Here, we propose that beta2m-free, peptide-free heavy chains support a helix-coil transition in the segment leading from the alpha2 domain to the alpha3 domain, facilitating rotation of backbone angles around residues 167/168, and allowing residues 169-181 (identical to a known B27 ligand) to loop around and occupy the molecule's own peptide-binding cleft. Such 'auto-display', occurring either within B27 molecules, or between B27 molecules, could provoke autoimmune attack.
Luthra-Guptasarma
Manni
M
Department of Immunopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160 012, India. mlg@glide.net.in
Singh
Balvinder
B
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000939:Epitopes; D005805:Genes, MHC Class I; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000378:metabolism*
D000939:Epitopes; D015796:HLA-B27 Antigen; D001613:beta 2-Microglobulin