PMID- 31740583 OWN - NLM STAT- MEDLINE DCOM- 20200622 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 294 IP - 52 DP - 2019 Dec 27 TI - Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation. PG - 20185-20195 LID - 10.1074/jbc.RA119.010257 [doi] AB - 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. CI - (c) 2019 Lim Kam Sian et al. FAU - Lim Kam Sian, Terry C C AU - Lim Kam Sian TCC AUID- ORCID: 0000-0001-7038-1214 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Indumathy, Saranjah AU - Indumathy S AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Halim, Hanim AU - Halim H AUID- ORCID: 0000-0002-3502-9351 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Greule, Anja AU - Greule A AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - EMBL Australia, Monash University, Clayton, Victoria 3800, Australia. FAU - Cryle, Max J AU - Cryle MJ AUID- ORCID: 0000-0002-9739-6157 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - EMBL Australia, Monash University, Clayton, Victoria 3800, Australia. FAU - Bowness, Paul AU - Bowness P AD - Botnar Research Centre, Nuffield, Department of Orthopaedics Rheumatology and Musculoskeletal Science, Nuffield Orthopaedic Centre, University of Oxford, Windmill Road, Headington, Oxford OX3 7LD, United Kingdom. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. AD - Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom. FAU - Gras, Stephanie AU - Gras S AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia stephanie.gras@monash.edu. AD - ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. FAU - Purcell, Anthony W AU - Purcell AW AUID- ORCID: 0000-0003-0532-8331 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia anthony.purcell@monash.edu. FAU - Schittenhelm, Ralf B AU - Schittenhelm RB AUID- ORCID: 0000-0001-8738-1878 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia ralf.schittenhelm@monash.edu. AD - Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. LA - eng SI - PDB/4G9G SI - PDB/6PYL SI - PDB/6PZ5 SI - PDB/6PYJ SI - PDB/6PYV SI - PDB/6PYW GR - MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191118 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (HLA-B*27:03 antigen) RN - 0 (HLA-B27 Antigen) SB - IM MH - Alleles MH - Cell Line MH - Crystallography, X-Ray MH - Dimerization MH - Genotype MH - HLA-B27 Antigen/chemistry/genetics/*metabolism MH - Humans MH - Mutagenesis, Site-Directed MH - Polymorphism, Genetic MH - Protein Stability MH - Protein Structure, Tertiary MH - Spondylitis, Ankylosing/metabolism/pathology PMC - PMC6937573 OTO - NOTNLM OT - Ankylosing spondylitis OT - HLA heavy chain homodimers OT - HLA-B*27:03 OT - HLA-B27 OT - X-ray crystallography OT - arthritis OT - autoimmune disease OT - crystallography OT - major histocompatibility complex (MHC) OT - single-nucleotide polymorphism (SNP) COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2019/11/20 06:00 MHDA- 2020/06/23 06:00 PMCR- 2020/12/27 CRDT- 2019/11/20 06:00 PHST- 2019/08/01 00:00 [received] PHST- 2019/10/31 00:00 [revised] PHST- 2019/11/20 06:00 [pubmed] PHST- 2020/06/23 06:00 [medline] PHST- 2019/11/20 06:00 [entrez] PHST- 2020/12/27 00:00 [pmc-release] AID - S0021-9258(20)30035-1 [pii] AID - RA119.010257 [pii] AID - 10.1074/jbc.RA119.010257 [doi] PST - ppublish SO - J Biol Chem. 2019 Dec 27;294(52):20185-20195. doi: 10.1074/jbc.RA119.010257. Epub 2019 Nov 18.