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Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. However, the exact involvement of HLA-B27 in disease initiation and progression remains unclear. The homodimer theory, which proposes that HLA-B27 heavy chains aberrantly form homodimers, is a central hypothesis that attempts to explain the role of HLA-B27 in disease pathogenesis. Here, we examined the ability of the eight most prevalent HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09) to form homodimers. We observed that HLA-B*27:03, a disease-associated HLA-B27 subtype, showed a significantly reduced ability to form homodimers compared with all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography and site-directed mutagenesis to unravel the molecular and structural mechanisms in HLA-B*27:03 that are responsible for its compromised ability to form homodimers. We show that polymorphism at position 59, which differentiates HLA-B*27:03 from all other allotypes, is responsible for its compromised ability to form homodimers. Indeed, histidine 59 in HLA-B*27:03 leads to a series of local conformational changes that act in concert to reduce the accessibility of the nearby cysteine 67, an essential amino acid residue for the formation of HLA-B27 homodimers. Considered together, the ability of both protective and disease-associated HLA-B27 allotypes to form homodimers and the failure of HLA-B*27:03 to form homodimers challenge the role of HLA-B27 homodimers in AS pathoetiology. Rather, this work implicates other features, such as peptide binding and antigen presentation, as pivotal mechanisms for disease pathogenesis.

Original publication

DOI

10.1074/jbc.RA119.010257

Type

Journal article

Journal

J biol chem

Publication Date

27/12/2019

Volume

294

Pages

20185 - 20195

Keywords

Ankylosing spondylitis, HLA heavy chain homodimers, HLA-B*27:03, HLA-B27, X-ray crystallography, arthritis, autoimmune disease, crystallography, major histocompatibility complex (MHC), single-nucleotide polymorphism (SNP), Alleles, Cell Line, Crystallography, X-Ray, Dimerization, Genotype, HLA-B27 Antigen, Humans, Mutagenesis, Site-Directed, Polymorphism, Genetic, Protein Stability, Protein Structure, Tertiary, Spondylitis, Ankylosing