Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation.
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)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
27 12 2019
27 12 2019
Historique:
received:
01
08
2019
revised:
31
10
2019
pubmed:
20
11
2019
medline:
23
6
2020
entrez:
20
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31740583
pii: S0021-9258(20)30035-1
doi: 10.1074/jbc.RA119.010257
pmc: PMC6937573
doi:
Substances chimiques
HLA-B*27:03 antigen
0
HLA-B27 Antigen
0
Banques de données
PDB
['4G9G', '6PYL', '6PZ5', '6PYJ', '6PYV', '6PYW']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20185-20195Subventions
Organisme : Medical Research Council
Pays : United Kingdom
Informations de copyright
© 2019 Lim Kam Sian et al.
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