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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.","bibjson":{"author":[{"initials":"TCC","lastname":"Lim Kam Sian","name":"Lim Kam Sian TCC"},{"initials":"S","lastname":"Indumathy","name":"Indumathy S"},{"initials":"H","lastname":"Halim","name":"Halim H"},{"initials":"A","lastname":"Greule","name":"Greule A"},{"initials":"MJ","lastname":"Cryle","name":"Cryle MJ"},{"initials":"P","lastname":"Bowness","name":"Bowness P"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"RB","lastname":"Schittenhelm","name":"Schittenhelm RB"}],"identifier":[{"id":"10.1074/jbc.RA119.010257","type":"doi"},{"id":"31740583","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Biol. Chem.","name":""},"pages":[null],"title":"Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation.","type":"article","url":"https://www.sciencedirect.com/science/article/abs/pii/S0021925820300351","volume":[null],"year":[2019]},"in_pmc":"N","in_pmce":"Y","open_access":"N"},"resolution":"1.45","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6pyv"},"rcsb":{"url":"https://www.rcsb.org/structure/6pyv"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*27:03 binding \"LRNQSVFNF\" at 1.45Å resolution","unique_chain_count":3}}