Structure-guided discovery of aminopeptidase ERAP1 variants capable of processing antigens with novel PC anchor specificities.
antigen processing kinetics
immunopeptidomes
molecular ruler mechanism
peptide carboxyl (PC) anchor
specificity SC subsite
Journal
Immunology
ISSN: 1365-2567
Titre abrégé: Immunology
Pays: England
ID NLM: 0374672
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
received:
04
04
2023
accepted:
06
10
2023
medline:
6
12
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
Endoplasmic reticulum aminopeptidase 1 (ERAP1) belongs to the oxytocinase subfamily of M1 aminopeptidases (M1APs), which are a diverse family of metalloenzymes involved in a wide range of functions and have been implicated in various chronic and infectious diseases of humans. ERAP1 trims antigenic precursors into correct sizes (8-10 residues long) for Major Histocompatibility Complex (MHC) presentation, by a unique molecular ruler mechanism in which it makes concurrent bindings to substrate N- and C-termini. We have previously determined four crystal structures of ERAP1 C-terminal regulatory domain (termed ERAP1_C domain) in complex with peptide carboxyl (PC)-ends that carry various anchor residues, and identified a specificity subsite for recognizing the PC anchor side chain, denoted as the SC subsite to follow the conventional notations: S1 site for P1, S2 site for P2, and so forth. In this study, we report studies on structure-guided mutational and hydrolysis kinetics, and peptide trimming assays to further examine the functional roles of this SC subsite. Most strikingly, a point mutation V737R results in a change of substrate preference from a hydrophobic to a negatively charged PC anchor residue; the latter is presumed to be a poor substrate for WT ERAP1. These studies validate the crystallographic observations that this SC subsite is directly involved in binding and recognition of the substrate PC anchor and presents a potential target to modulate MHC-restricted immunopeptidomes.
Substances chimiques
Aminopeptidases
EC 3.4.11.-
Antigens
0
Peptides
0
Minor Histocompatibility Antigens
0
ERAP1 protein, human
EC 3.4.11.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
131-145Subventions
Organisme : National Institutes of General Medicine
ID : GM128152
Informations de copyright
© 2023 The Authors. Immunology published by John Wiley & Sons Ltd.
Références
Rawlings ND, Bateman A. How to use the MEROPS database and website to help understand peptidase specificity. Protein Sci. 2021;30(1):83-92.
Drinkwater N, Lee J, Yang W, Malcolm TR, McGowan S. M1 aminopeptidases as drug targets: broad applications or therapeutic niche? FEBS J. 2017;284(10):1473-1488.
Peer WA. The role of multifunctional M1 metallopeptidases in cell cycle progression. Ann Bot. 2011;107(7):1171-1181.
Cifaldi L, Romania P, Lorenzi S, Locatelli F, Fruci D. Role of endoplasmic reticulum aminopeptidases in health and disease: from infection to cancer. Int J Mol Sci. 2012;13(7):8338-8352.
Alvarez-Navarro C, Lopez de Castro JA. ERAP1 in ankylosing spondylitis: genetics, biology and pathogenetic role. Curr Opin Rheumatol. 2013;25(4):419-425.
Alvarez-Navarro C, Lopez de Castro JA. ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Mol Immunol. 2014;57(1):12-21.
Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105(16):1172-1187.
Agrawal N, Brown MA. Genetic associations and functional characterization of M1 aminopeptidases and immune-mediated diseases. Genes Immun. 2014;15(8):521-527.
Fruci D, Romania P, D'Alicandro V, Locatelli F. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases. Tissue Antigens. 2014;84(2):177-186.
Lopez de Castro JA, Alvarez-Navarro C, Brito A, Guasp P, Martin-Esteban A, Sanz-Bravo A. Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: towards a unifying view. Mol Immunol. 2016;77:193-204.
Serwold T, Gonzalez F, Kim J, Jacob R, Shastri N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature. 2002;419(6906):480-483.
Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL, et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol. 2002;3(12):1169-1176.
Tanioka T, Hattori A, Masuda S, Nomura Y, Nakayama H, Mizutani S, et al. Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem. 2003;278(34):32275-32283.
Saveanu L, Carroll O, Hassainya Y, van Endert P. Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation. Immunol Rev. 2005;207:42-59.
Tsujimoto M, Hattori A. The oxytocinase subfamily of M1 aminopeptidases. Biochim Biophys Acta. 2005;1751(1):9-18.
Hanson AL, Morton CJ, Parker MW, Bessette D, Kenna TJ. The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease. Hum Immunol. 2019;80(5):281-289.
Babaie F, Hosseinzadeh R, Ebrazeh M, Seyfizadeh N, Aslani S, Salimi S, et al. The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: new insights and perspective. Mol Immunol. 2020;121:7-19.
Yang X, Garner LI, Zvyagin IV, Paley MA, Komech EA, Jude KM, et al. Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides. Nature. 2022;612:771-777.
Chang SC, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism. Proc Natl Acad Sci U S A. 2005;102(47):17107-17112.
Nguyen TT, Chang SC, Evnouchidou I, York IA, Zikos C, Rock KL, et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nat Struct Mol Biol. 2011;18(5):604-613.
Guo H-C, Jardetzky TS, Garrett TPJ, Lane WS, Strominger JL, Wiley DC. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle. Nature. 1992;360(6402):364-366.
Silver ML, Guo H-C, Strominger JL, Wiley DC. Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature. 1992;360(6402):367-369.
Evnouchidou I, Momburg F, Papakyriakou A, Chroni A, Leondiadis L, Chang SC, et al. The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1. PloS One. 2008;3(11):e3658.
Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics. 1999;50(3-4):213-219.
Ascher DB, Cromer BA, Morton CJ, Volitakis I, Cherny RA, Albiston AL, et al. Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain. Biochemistry. 2011;50(13):2611-2622.
Hermans SJ, Ascher DB, Hancock NC, Holien JK, Michell BJ, Chai SY, et al. Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. Protein Sci. 2015;24(2):190-199.
Mpakali A, Saridakis E, Giastas P, Maben Z, Stern LJ, Larhed M, et al. Structural basis of inhibition of insulin-regulated aminopeptidase by a macrocyclic peptidic inhibitor. ACS Med Chem Lett. 2020;11(7):1429-1434.
Gandhi A, Lakshminarasimhan D, Sun Y, Guo H-C. Structural insights into the molecular ruler mechanism of the endoplasmic reticulum aminopeptidase ERAP1. Sci Rep. 2011;1:186.
Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005;6(7):689-697.
Lorente E, Barriga A, Johnstone C, Mir C, Jimenez M, Lopez D. Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases. PloS One. 2013;8(11):e79596.
Martín-Esteban A, Rodriguez JC, Peske D, Lopez de Castro JA, Shastri N, Sadegh-Nasseri S. The ER aminopeptidases, ERAP1 and ERAP2, synergize to self-modulate their respective activities. Front Immunol. 2022;13:1066483.
Sui L, Gandhi A, Guo H-C. Crystal structure of a polypeptide's C-terminus in complex with the regulatory domain of ER aminopeptidase 1. Mol Immunol. 2016;80:41-49.
Sui L, Guo H-C. ERAP1 binds peptide C-termini of different sequences and/or lengths by a common recognition mechanism. Immunobiology. 2021;226(4):152112.
Harvey D, Pointon JJ, Evans DM, Karaderi T, Farrar C, Appleton LH, et al. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet. 2009;18(21):4204-4212.
Stamogiannos A, Koumantou D, Papakyriakou A, Stratikos E. Effects of polymorphic variation on the mechanism of endoplasmic reticulum aminopeptidase 1. Mol Immunol. 2015;67(2 Pt B):426-435.
Mpakali A, Giastas P, Mathioudakis N, Mavridis IM, Saridakis E, Stratikos E. Structural basis for antigenic peptide recognition and processing by endoplasmic reticulum (ER) aminopeptidase 2. J Biol Chem. 2015;290(43):26021-26032.
Giastas P, Mpakali A, Papakyriakou A, Lelis A, Kokkala P, Neu M, et al. Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1. Proc Natl Acad Sci U S A. 2019;116:26709-26716.
Rotzschke O, Falk K, Stevanovic S, Jung G, Walden P, Rammensee HG. Exact prediction of a natural T cell epitope. Eur J Immunol. 1991;21(11):2891-2894.
Haeckel R, Hess B, Lauterborn W, Wuster KH. Purification and allosteric properties of yeast pyruvate kinase. Hoppe Seylers Z Physiol Chem. 1968;349(5):699-714.
Hathaway JA, Atkinson DE. The effect of Adenylic acid on yeast nicotinamide adenine dinucleotide isocitrate dehydrogenase, a possible metabolic control mechanism. J Biol Chem. 1963;238:2875-2881.
Okazaki R, Kornberg A. Deoxythymidine kinase of Escherichia Coli. I. Purification and some properties of the enzyme. J Biol Chem. 1964;239:269-274.
Reeves E, Colebatch-Bourn A, Elliott T, Edwards CJ, James E. Functionally distinct ERAP1 allotype combinations distinguish individuals with ankylosing spondylitis. Proc Natl Acad Sci U S A. 2014;111(49):17594-17599.
Hutchinson JP, Temponeras I, Kuiper J, Cortes A, Korczynska J, Kitchen S, et al. Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties. J Biol Chem. 2021;296:100443.
Kochan G, Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, et al. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci U S A. 2011;108(19):7745-7750.
Maben Z, Arya R, Georgiadis D, Stratikos E, Stern LJ. Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. Nat Commun. 2021;12(1):5302.
Stamogiannos A, Maben Z, Papakyriakou A, Mpakali A, Kokkala P, Georgiadis D, et al. Critical role of interdomain interactions in the conformational change and catalytic mechanism of endoplasmic reticulum aminopeptidase 1. Biochemistry. 2017;56(10):1546-1558.
Rotzschke O, Falk K, Stevanovic S, Gnau V, Jung G, Rammensee HG. Dominant aromatic/aliphatic C-terminal anchor in HLA-B*2702 and B*2705 peptide motifs. Immunogenetics. 1994;39(1):74-77.
Giastas P, Neu M, Rowland P, Stratikos E. High-resolution crystal structure of endoplasmic reticulum aminopeptidase 1 with bound Phosphinic transition-state analogue inhibitor. ACS Med Chem Lett. 2019;10(5):708-713.
Liddle J, Hutchinson JP, Kitchen S, Rowland P, Neu M, Cecconie T, et al. Targeting the regulatory site of ER aminopeptidase 1 leads to the discovery of a natural product modulator of antigen presentation. J Med Chem. 2020;63(6):3348-3358.
Maben Z, Arya R, Rane D, An WF, Metkar S, Hickey M, et al. Discovery of selective inhibitors of endoplasmic reticulum aminopeptidase 1. J Med Chem. 2020;63(1):103-121.
Reeves E, Islam Y, James E. ERAP1: a potential therapeutic target for a myriad of diseases. Expert Opin Ther Targets. 2020;24(6):535-544.
D'Amico S, Tempora P, Melaiu O, Lucarini V, Cifaldi L, Locatelli F, et al. Targeting the antigen processing and presentation pathway to overcome resistance to immune checkpoint therapy. Front Immunol. 2022;13:948297.
Sui L, Gandhi A, Guo H-C. Single-chain expression and crystallization of an antigenic C-terminus in complex with the regulatory domain of ER aminopeptidase 1. Crys Struct Theory Appl. 2015;4:47-52.
Sui L, Guo H-C. Enhanced recombinant expression and purification of human IRAP for biochemical and crystallography studies. Biochem Biophys Rep. 2021;27:101042.