Here's a bit of background information on what ERAP1 does.
ERAP1 stands for Endoplasmic Reticulum Amino Peptidase 1
It is located on Chromosome 5q15 and is composed of 20 Exons (Transcription Length 5,488 bps Translational Length 948 aa) and 19 Introns (Transcription length ~42 kb (total 47.28 kb).
The association of ERAP1 and disease is a major breakthrough in AS research. The gene product has two known functions, firstly within the Endoplasmic Reticulum of a cell, ERAP1 (in association with the closely related ERAP2) is responsible for trimming short peptides to optimal length for MHC Class I presentation. Since AS is primarily an MHC Class I mediated disease, this has implications favouring mechanisms of disease generation that involve abnormalities of peptide presentation. The second known function of ERAP1 is (when secreted), ectodomain shedding of cell surface cytokine receptors of the pro-inflammatory cytokines IL-1 (IL1R2, decoy IL-1 receptor), IL-6 (IL6Rα) and TNFα (TNFRSF1A).
So far there is no evidence for the association of ERAP1 with Crohn’s Disease or Ulcerative colitis, both of which are not Class I mediated diseases; whereas up-regulation of IL-1, IL-6, TNFα and IL-23 is a feature of these conditions. This would suggest that it is the peptide trimming function of ERAP1, and not cytokine receptor cleavage, that explains the mechanism of association with AS.
ERAP1 is a Zn containing metallopeptidase that is a member of the ‘M1/gluzincin family’ of peptidases. It is most clearly related to ERAP2 and P-LAP and together ERAP1, ERAP2 and P-LAP form the oxytocinase subfamily of M1 peptidases. All three have highly conserved C-terminal domains that allow the recognition and cleaving of peptide precursors. ERAP1 has a modular organisation that explains its molecular ruler mechanism. When a precursor peptide’s C-terminus is bound to ERAP1’s regulatory domain it induces a conformational change of ERAP1 from the open to the closed position thereby allosterically activating the catalytic zinc site 30 Angstroms distant which trims the last amino acid, provided the precursor peptide is long enough to reach the catalytic site. It has been shown that peptides shorter than 8 residues are not long enough to be efficiently trimmed by ERAP1. Longer antigenic precursors could be accommodated by bulging or zig-zagging of the middle of the peptide within the binding groove.
The structure of the soluble domain of ERAP1 has recently been determined. A central wide channel leads to the active site Zn(II) and it is the obvious candidate to accommodate the peptide substrate. The enzyme undergoes conformational changes which represent snapshots of the catalytic cycle. Interactions between ERAP1 and the peptide mainly involve hydrophobic and van der Waal contacts, plus a H-bond contact with the carboxylate end of the peptide. ERAP1 has four domains: domain I (residues 46-254); domain II (residues 255-529, which contains the catalytic site; domain III (residues 530-614 forming a β sandwich with two β-sheets) and domain IV (residues 615-940 forming a large bowl shaped α-helix domain containing 16 α-helices). The ERAP1 regulatory domain is composed of sub-domains III and IV which can interact with domain II through conformational changes to either shield or expose the catalytic site.
For proteolysis to occur domain IV must swing back over the catalytic domain, and in so doing activate the protease. After the N-terminal residue is cleaved, the cavity must open in order to release the products, which can then bind for another round of proteolysis. This is supported by peptide intermediates when monitoring the shortening of the ERAP substrates. The non-processive nature of peptide trimming is a result of N- and C-terminal anchoring, requiring active site closure, and subsequent release of the N-terminally cleaved amino acid residue. For a new round of cleavage to occur, the trimmed peptide needs also to be released to allow another round of productive binding due to the necessity to attach the free amino terminus at the S1 binding site. Note that all trimming intermediate products can be observed with different maxima at successive time points. ERAP1 functions as a molecular ruler because cleavage efficiency is significantly reduced for peptides shorter than eight residues. Proteolysis only occurs if there is a secondary binding site within the internal cavity where the C-terminal part of the substrate is bound and hence this defines the minimal product length. The internal cavity is large enough to accommodate large peptides (9-15 peptides) but peptides shorter than 8 or 9 peptides are not cleaved because both binding sites cannot be occupied. The 8-mer is still able to bind ERAP1 but is not further processed and acts as a competitor for the 9-mer.
