| Structural highlights
3qnf is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 2xdt |
| Gene: | ERAP1, APPILS, ARTS1, KIAA0525, UNQ584/PRO1154 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ERAP1_HUMAN] Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.[1] [2] [3]
Publication Abstract from PubMed
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.
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 KL, Brown MA, Bowness P, Wordsworth P, Kessler BM, Oppermann U Proc Natl Acad Sci U S A. 2011 May 10;108(19):7745-50. Epub 2011 Apr 20. PMID:21508329[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, van Endert PM. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005 Jul;6(7):689-97. Epub 2005 May 22. PMID:15908954 doi:http://dx.doi.org/10.1038/ni1208
- ↑ Chang SC, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17107-12. Epub 2005 Nov 14. PMID:16286653 doi:http://dx.doi.org/0500721102
- ↑ Nguyen TT, Chang SC, Evnouchidou I, York IA, Zikos C, Rock KL, Goldberg AL, Stratikos E, Stern LJ. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nat Struct Mol Biol. 2011 May;18(5):604-13. Epub 2011 Apr 10. PMID:21478864 doi:10.1038/nsmb.2021
- ↑ Kochan G, Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, von Delft F, Kavanagh KL, Brown MA, Bowness P, Wordsworth P, Kessler BM, Oppermann U. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7745-50. Epub 2011 Apr 20. PMID:21508329 doi:10.1073/pnas.1101262108
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