期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 19, 页码 7745-7750出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101262108
关键词
antigen presentation; ERAP1 mechanism; MHC restriction
资金
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck and Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- National Health and Medical Research Council (Australia)
- Arthritis Research UK [19536, 18599, 18797]
- Wellcome Trust [076113]
- National Institute for Health Research Oxford Comprehensive Biomedical Research Centre [A91202]
- National Ankylosing Spondylitis Society (UK)
- Action Medical Research Grant [208701, SC039284]
- Oxford National Institute for Health Research Biomedical Research Unit
- Medical Research Council [G1000800g] Funding Source: researchfish
- Versus Arthritis [18599] Funding Source: researchfish
Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)(18)-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K(528)R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.
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