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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.

Original publication

DOI

10.1073/pnas.1101262108

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

05/2011

Volume

108

Pages

7745 - 7750

Addresses

Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, United Kingdom.

Keywords

Humans, Spondylitis, Ankylosing, Aminopeptidases, Recombinant Proteins, HLA-B27 Antigen, Minor Histocompatibility Antigens, Crystallography, X-Ray, Amino Acid Substitution, Mutagenesis, Site-Directed, Antigen Presentation, Protein Processing, Post-Translational, Amino Acid Sequence, Catalytic Domain, Protein Conformation, Protein Structure, Tertiary, Polymorphism, Single Nucleotide, Models, Molecular