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

Kochan, Grazyna, Krojer, Tobias, Harvey, David, Fischer, Roman, Chen, Liye, Vollmar, Melanie, von Delft, Frank, Kavanagh, Kathryn L., Brown, Matthew A., Bowness, Paul, Wordsworth, Paul, Kessler, Benedikt M. and Oppermann, Udo (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: 7745-7750. doi:10.1073/pnas.1101262108


Author Kochan, Grazyna
Krojer, Tobias
Harvey, David
Fischer, Roman
Chen, Liye
Vollmar, Melanie
von Delft, Frank
Kavanagh, Kathryn L.
Brown, Matthew A.
Bowness, Paul
Wordsworth, Paul
Kessler, Benedikt M.
Oppermann, Udo
Title Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2011-05-10
Sub-type Article (original research)
DOI 10.1073/pnas.1101262108
Open Access Status Not Open Access
Volume 108
Issue 19
Start page 7745
End page 7750
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Collection year 2012
Language eng
Formatted abstract
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 K528R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.
Keyword Antigen presentation
ERAP1 mechanism
MHC restriction
Leukotriene A(4) hydrolase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
 
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