Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Kochan, G., Krojer, T., Harvey, D., Fischer, R., Chen, L., Vollmar, M., Von Delft, F., Kavanagh, K. L., Brown, Matthew A., Bowness, P., Wordsworth, P., Kessler, B. M., & Oppermann, U. (2011) Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proceedings of the National Academy of Sciences of the United States of America, 108(19), pp. 7745-7750.

View at publisher (open access)


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 528R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.

Impact and interest:

91 citations in Scopus
Search Google Scholar™
85 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 89373
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :70
Export Date: 21 September 2015
Correspondence Address: Oppermann, U.; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, United Kingdom; email:
Keywords: Antigen presentation, ERAP1 mechanism, MHC restriction, endoplasmic reticulum aminopeptidase 1, metalloproteinase, unclassified drug, zinc binding protein, amino terminal sequence, article, catalysis, crystal structure, endoplasmic reticulum, enzyme active site, enzyme conformation, enzyme structure, human, priority journal, protein motif, protein processing, structure activity relation, Amino Acid Sequence, Amino Acid Substitution, Aminopeptidases, Catalytic Domain, Crystallography, X-Ray, HLA-B27 Antigen, Humans, Models, Molecular, Mutagenesis, Site-Directed, Polymorphism, Single Nucleotide, Protein Conformation, Protein Processing, Post-Translational, Protein Structure, Tertiary, Recombinant Proteins, Spondylitis, Ankylosing
DOI: 10.1073/pnas.1101262108
ISSN: 00278424
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: The Author
Deposited On: 22 Oct 2015 01:37
Last Modified: 26 Feb 2016 03:10

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page