Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation
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 HL...
| Hauptverfasser: | , , , , , , , , , |
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| Format: | Journal article |
| Sprache: | English |
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American Society for Biochemistry and Molecular Biology
2019
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| _version_ | 1826306645252112384 |
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| author | Lim Kam Sian, TCC Indumathy, S Halim, H Greule, A Cryle, MJ Bowness, P Rossjohn, J Gras, S Purcell, AW Schittenhelm, RB |
| author_facet | Lim Kam Sian, TCC Indumathy, S Halim, H Greule, A Cryle, MJ Bowness, P Rossjohn, J Gras, S Purcell, AW Schittenhelm, RB |
| author_sort | Lim Kam Sian, TCC |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:51:06Z |
| format | Journal article |
| id | oxford-uuid:fc95d423-db8c-4fba-88a5-9cfaa1915a91 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:51:06Z |
| publishDate | 2019 |
| publisher | American Society for Biochemistry and Molecular Biology |
| record_format | dspace |
| spelling | oxford-uuid:fc95d423-db8c-4fba-88a5-9cfaa1915a912022-03-27T13:22:01ZAllelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fc95d423-db8c-4fba-88a5-9cfaa1915a91EnglishSymplectic ElementsAmerican Society for Biochemistry and Molecular Biology2019Lim Kam Sian, TCCIndumathy, SHalim, HGreule, ACryle, MJBowness, PRossjohn, JGras, SPurcell, AWSchittenhelm, RBExpression 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. |
| spellingShingle | Lim Kam Sian, TCC Indumathy, S Halim, H Greule, A Cryle, MJ Bowness, P Rossjohn, J Gras, S Purcell, AW Schittenhelm, RB Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title | Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title_full | Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title_fullStr | Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title_full_unstemmed | Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title_short | Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation |
| title_sort | allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen b27 homodimer formation |
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