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.
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.
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|Item Type:||Journal Article|
|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: firstname.lastname@example.org
|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|
|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|
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