Endoplasmic Reticulum Aminopeptidase 1 (ERAP1; ERAAP) belongs to the M1 subfamily of zinc-dependent metalopeptidases. This protein is a multifunctional aminopeptidase involved in regulation of innate immune responses and inflammation. Its best-characterised function is the final trimming of peptides for MHC class I presentation. ERAP1 exerts its activity towards peptides between 20-8 aa, with preference for peptides containing hydrophobic carboxy-terminal aminoacids, particularly leucine (Saric et al., 2002; Chang
et al., 2005), playing a central role in immunodominance (York
et al., 2006). ERAP1 has been reported to bind to cytokine receptors at the cell surface such as IFNR1 (Cui
et al., 2002), IL6R1 (Cui
et al., 2003) and IL1RII (decoy IL1 receptor) (Cui
et al., 2003), promoting their ectodomain shedding. ERAP1 is additionally involved in regulating blood pressure through the inactivation of angiotensin II and conversion of kallidin to bradikinin in the kidney (Tsujimoto M and Hattori A., 2005). ERAP1 has also been reported to play other roles such as in angionesis (Miyashita
et al., 2003), and several polymorphisms are associated to diseases with an autoimmune aetiology such as ankylosing spondylitis and inflammatory arthritis (Brown M., 2009; Harvey
et al., 2009). Additionally, it has also been shown that ERAP1/2 imbalance and downregulation may favour tumour escape by avoiding immunological detection of transformed cancerous cells (Fruci
et al., 2008).
Here we present the structure of full-length ERAP1 in the unliganded open conformation at 3.0Å resolution (3QNF).
