{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a key enzyme in the antigen‐processing pathway that trims N‐extended peptide precursors in the endoplasmic reticulum to generate optimal ligands for binding to major histocompatibility complex (MHC) class I molecules."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Although it operates in parallel with its homolog ERAP1, ERAP2 displays distinct substrate specificity and catalytic properties – for example, certain polymorphic variants (such as those affecting residue 392) markedly accelerate the removal of hydrophobic N‐terminal residues from antigenic precursors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Structural analyses have provided insights into these differences and revealed that ERAP2 can form heterodimeric complexes with ERAP1, a configuration that enhances peptide trimming efficiency while maintaining a diversified pool of antigenic peptides."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, evolutionary and expression studies indicate that ERAP2 is subject to balancing selection, which generates distinct haplotypes and splice variants; these in turn modulate its expression and influence the surface display of MHC class I molecules, thereby impacting immune surveillance and disease susceptibility. In fact, altered ERAP2 expression and function have been implicated in several immune‐mediated conditions—including Birdshot chorioretinopathy, preeclampsia, and ankylosing spondylitis—reflecting its role as a peptide editor that fine‐tunes the antigenic repertoire."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": " Collectively, these studies underscore the pivotal function of ERAP2 in determining the quality of antigen presentation and suggest that targeting its activity may hold promise for therapeutic intervention in disorders associated with aberrant immune responses.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Loredana Saveanu, Oliver Carroll, Vivian Lindo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni1208"}], "href": "https://doi.org/10.1038/ni1208"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15908954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15908954"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aida M Andrés, Megan Y Dennis, Warren W Kretzschmar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1001157"}], "href": "https://doi.org/10.1371/journal.pgen.1001157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20976248"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20976248"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Irini Evnouchidou, James Birtley, Sergey Seregin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1200918"}], "href": "https://doi.org/10.4049/jimmunol.1200918"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22837489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22837489"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Efthalia Zervoudi, Athanasios Papakyriakou, Dimitra Georgiadou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20102049"}], "href": "https://doi.org/10.1042/BJ20102049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21314638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21314638"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "James R Birtley, Emmanuel Saridakis, Efstratios Stratikos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi201230p"}], "href": "https://doi.org/10.1021/bi201230p"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22106953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22106953"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hanna Chen, Lenong Li, Mirjana Weimershaus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep28902"}], "href": "https://doi.org/10.1038/srep28902"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27514473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27514473"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jonas J W Kuiper, Jessica Van Setten, Stephan Ripke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu307"}], "href": "https://doi.org/10.1093/hmg/ddu307"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24957906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24957906"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Adrian Martín-Esteban, Alejandro Sanz-Bravo, Pablo Guasp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Autoimmun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaut.2016.12.008"}], "href": "https://doi.org/10.1016/j.jaut.2016.12.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28063628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28063628"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Adrian Martín-Esteban, Pablo Guasp, Eilon Barnea, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional Interaction of the Ankylosing Spondylitis-Associated Endoplasmic Reticulum Aminopeptidase 2 With the HLA-B*27 Peptidome in Human Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheumatol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.39734"}], "href": "https://doi.org/10.1002/art.39734"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27110896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27110896"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jonas J W Kuiper, Jessica van Setten, Matthew Devall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy319"}], "href": "https://doi.org/10.1093/hmg/ddy319"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30215709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30215709"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Aimee L Hanson, Thomas Cuddihy, Katelin Haynes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Variants in ERAP1 and ERAP2 Associated With Immune-Mediated Diseases Influence Protein Expression and the Isoform Profile."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheumatol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.40369"}], "href": "https://doi.org/10.1002/art.40369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29108111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29108111"}]}]}]}