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  • br Polymorphic variation ERAP is

    2024-02-07


    Polymorphic variation ERAP1 is polymorphic and several single nucleotide polymorphisms (SNPs) in its gene that encode amino Orantinib sale changes have been associated with predisposition to a variety of diseases, ranging from viral infections to cancer and autoimmunity (Alvarez-Navarro and Lopez de Castro, 2014; Stratikos et al., 2014). Functional studies on ERAP1 alleles have suggested that disease-associated SNPs affect enzymatic function and specificity (Evnouchidou et al., 2011; Reeves et al., 2013; Stamogiannos et al., 2015). Indeed, experiments comparing cell lines harboring different ERAP1 allelic forms have revealed distinct effects on the cellular immunopeptidome and provided hints on the pathogenesis of HLA-associated autoimmunity (Martin-Esteban et al., 2017; Guasp et al., 2017; Lopez de Castro et al., 2016). ERAP2 also harbors common coding SNPs although fewer than for ERAP1. The ERAP2 SNP rs2248374 has been found to regulate the expression levels of the enzyme via nonsense RNA mediated decay (Andres et al., 2010) and SNP rs2549782 codes for a substitution near the catalytic site of the enzyme, affecting both activity and specificity (Evnouchidou et al., 2012). ERAP2 SNPs have been associated with predisposition to autoimmunity, preeclampsia and resistance to HIV infection, possibly due to changes in antigen processing and presentation (Johnson et al., 2009; Vanhille et al., 2013; Cagliani et al., 2010; Kuiper et al., 2014).
    Basic and unique enzymatic properties ERAP1 is a member of the M1 family of aminopeptidases, which utilize a bound zinc ion to hydrolyze the amino terminal peptide bond of a substrate (Hattori et al., 1999; Schomburg et al., 2000). This class of enzyme is found in bacteria and eukaryotes, with myriad substrate specificities and physiological roles, ranging from metabolism to neurotransmitter and hormone degradation, to immune function and antigen processing (Danziger, 2008; Peer, 2011; Bhosale et al., 2013; Rawlings and Barrett, 1993). This versatility is possible due to the large size of the substrate binding pocket, which extends away from the active site and can accommodate substrates up to 20 amino acids long in the case of ERAP1 (Chang et al., 2005). Different M1 family members have different preferences for substrate N-terminal residues, with ERAP1 exhibiting broad specificity for aliphatic residues (Zervoudi et al., 2011). Along with the length of the substrate, ERAP1 exhibits preferences for particular side chains at particular positions, but in a more degenerate pattern than other more specific proteases. Two notable preferences are for a bulky aliphatic or aromatic group at S1’ (amino-terminal to the cleavage site), and for either a large hydrophobic group or a basic group at Somega, (carboxy-terminal side chain) (Zervoudi et al., 2011; Evnouchidou et al., 2008). Unlike other M1 aminopeptidases, ERAP1 has a strong preference for trimming substrates longer than eight or nine amino acids (Chang et al., 2005; York et al., 2002). This activity is well suited for efficient generation of peptides of length suitable for loading onto MHCI proteins. A mechanism for peptide-length dependent regulation of ERAP1 aminopeptidase activity has been proposed, based on cooperativity and allosteric activation observed for short but not full-length peptide substrates (Nguyen et al., 2011). The model postulates a regulatory site distinct from the active site that can be accessed by long substrates, with binding to this site favoring adoption of a closed conformation with increased catalytic activity (Nguyen et al., 2011). Crystal structures of a complex between the C-terminal domain of ERAP1 and a C-terminus of peptides presented in fusion with the same domain suggested a possible location of this regulatory site (Sui et al., 2016).
    Known crystal structures Crystal structures have been reported for ERAP1, ERAP2, and IRAP, the members of the oxytocinase subfamily of M1 aminopeptidases, all of which have roles in antigen presentation. The structures confirmed that these enzymes closely resemble the other M1 aminopeptidases structurally. They consist of four domains. Domain I is a mixed all-beta sandwich present in other aminopeptidases that caps off the amino-terminal side of active site. Domain II contains the active-site zinc in a thermolysin-like α/β fold. Domain III is an Ig-like domain unique to the M1 family. Domain IV contains 8 Armadillo-like helix-turn-helix repeats forming a bowl-like structure (Gandhi et al., 2011).