Reference |
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Reference Type | Literature | IEDB_Reference:1033452 |
Title | Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome. | |
Authors | Alejandro Sanz-Bravo; Carlos Alvarez-Navarro; Adrian Martín-Esteban; Eilon Barnea; Arie Admon; José A López de Castro | |
Affiliations | From the ‡Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain; §Instituto de Inmunología, Facultad de Medicina, Universidad Austral del Chile, and Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Valdivia, Chile; ¶Faculty of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel; aldecastro@cbm.csic.es. | |
Journal | Mol Cell Proteomics | |
Year | 2018 | |
Abstract | The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it further decreased ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, because of distinct effects on trimming of nonamers compared with longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, because of the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals. | |
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