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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 108 7745-50 (2011)
Cited: 144 times
EuropePMC logo PMID: 21508329

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 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.

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  3. Marine Invertebrates: A Promissory Still Unexplored Source of Inhibitors of Biomedically Relevant Metallo Aminopeptidases Belonging to the M1 and M17 Families. Pascual Alonso I, Almeida García F, Valdés Tresanco ME, Arrebola Sánchez Y, Ojeda Del Sol D, Sánchez Ramírez B, Florent I, Schmitt M, Avilés FX. Mar Drugs 21 279 (2023)

Articles - 3qnf mentioned but not cited (6)

  1. 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 108 7745-7750 (2011)
  2. Structural basis for multifunctional roles of mammalian aminopeptidase N. Chen L, Lin YL, Peng G, Li F. Proc Natl Acad Sci U S A 109 17966-17971 (2012)
  3. A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases. López-Pelegrín M, Cerdà-Costa N, Martínez-Jiménez F, Cintas-Pedrola A, Canals A, Peinado JR, Marti-Renom MA, López-Otín C, Arolas JL, Gomis-Rüth FX. J Biol Chem 288 21279-21294 (2013)
  4. Functional interpretation of a non-gut hemocoelic tissue aminopeptidase N (APN) in a lepidopteran insect pest Achaea janata. Ningshen TJ, Aparoy P, Ventaku VR, Dutta-Gupta A. PLoS One 8 e79468 (2013)
  5. Crystallization and preliminary X-ray diffraction analysis of human endoplasmic reticulum aminopeptidase 2. Ascher DB, Polekhina G, Parker MW. Acta Crystallogr Sect F Struct Biol Cryst Commun 68 468-471 (2012)
  6. Structure of puromycin-sensitive aminopeptidase and polyglutamine binding. Madabushi S, Chow KM, Song ES, Goswami A, Hersh LB, Rodgers DW. PLoS One 18 e0287086 (2023)


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