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Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1.

Giastas P, Mpakali A, Papakyriakou A, Lelis A, Kokkala P, Neu M, Rowland P, Liddle J, Georgiadis D, Stratikos E
Proc Natl Acad Sci U S A 116 26709-26716 (2019)
Cited: 23 times
EuropePMC logo PMID: 31843903

Abstract

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that optimizes the peptide cargo of major histocompatibility class I (MHC-I) molecules and regulates adaptive immunity. It has unusual substrate selectivity for length and sequence, resulting in poorly understood effects on the cellular immunopeptidome. To understand substrate selection by ERAP1, we solved 2 crystal structures of the enzyme with bound transition-state pseudopeptide analogs at 1.68 Å and 1.72 Å. Both peptides have their N terminus bound at the active site and extend away along a large internal cavity, interacting with shallow pockets that can influence selectivity. The longer peptide is disordered through the central region of the cavity and has its C terminus bound in an allosteric pocket of domain IV that features a carboxypeptidase-like structural motif. These structures, along with enzymatic and computational analyses, explain how ERAP1 can select peptides based on length while retaining the broad sequence-specificity necessary for its biological function.

Reviews - 6ryf mentioned but not cited (1)

  1. Phosphinic Peptides as Tool Compounds for the Study of Pharmacologically Relevant Zn-Metalloproteases. Georgiadis D, Skoulikas N, Papakyriakou A, Stratikos E. ACS Pharmacol Transl Sci 5 1228-1253 (2022)

Articles - 6ryf mentioned but not cited (2)

  1. Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1. Giastas P, Mpakali A, Papakyriakou A, Lelis A, Kokkala P, Neu M, Rowland P, Liddle J, Georgiadis D, Stratikos E. Proc Natl Acad Sci U S A 116 26709-26716 (2019)
  2. Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. Maben Z, Arya R, Georgiadis D, Stratikos E, Stern LJ. Nat Commun 12 5302 (2021)


Reviews citing this publication (3)

  1. HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole. Kuiper JJW, Venema WJ. Front Immunol 11 599558 (2020)
  2. From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase. Hallberg M, Larhed M. Front Pharmacol 11 590855 (2020)
  3. To Be or Not to Be: The Case of Endoplasmic Reticulum Aminopeptidase 2. Kuśnierczyk P. Front Immunol 13 902567 (2022)

Articles citing this publication (17)

  1. A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1. Mavridis G, Arya R, Domnick A, Zoidakis J, Makridakis M, Vlahou A, Mpakali A, Lelis A, Georgiadis D, Tampé R, Papakyriakou A, Stern LJ, Stratikos E. J Biol Chem 295 7193-7210 (2020)
  2. Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties. Hutchinson JP, Temponeras I, Kuiper J, Cortes A, Korczynska J, Kitchen S, Stratikos E. J Biol Chem 296 100443 (2021)
  3. ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation. Arakawa A, Reeves E, Vollmer S, Arakawa Y, He M, Galinski A, Stöhr J, Dornmair K, James E, Prinz JC. J Immunol 207 2235-2244 (2021)
  4. ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29. Venema WJ, Hiddingh S, de Boer JH, Claas FHJ, Mulder A, den Hollander AI, Stratikos E, Sarkizova S, van der Veken LT, Janssen GMC, van Veelen PA, Kuiper JJW. Front Immunol 12 634441 (2021)
  5. ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function. D'Amico S, D'Alicandro V, Compagnone M, Tempora P, Guida G, Romania P, Lucarini V, Melaiu O, Falco M, Algeri M, Pende D, Cifaldi L, Fruci D. Front Immunol 12 778103 (2021)
  6. Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation. Papakyriakou A, Mpakali A, Stratikos E. Front Immunol 13 863529 (2022)
  7. ERAP2 Inhibition Induces Cell-Surface Presentation by MOLT-4 Leukemia Cancer Cells of Many Novel and Potentially Antigenic Peptides. Temponeras I, Stamatakis G, Samiotaki M, Georgiadis D, Pratsinis H, Panayotou G, Stratikos E. Int J Mol Sci 23 1913 (2022)
  8. Discovery and Optimization of a Series of Benzofuran Selective ERAP1 Inhibitors: Biochemical and In Silico Studies. Deddouche-Grass S, Andouche C, Bärenz F, Halter C, Hohwald A, Lebrun L, Membré N, Morales R, Muzet N, Poirot M, Reynaud M, Roujean V, Weber F, Zimmermann A, Heng R, Basse N. ACS Med Chem Lett 12 1137-1142 (2021)
  9. ERAP1 binds peptide C-termini of different sequences and/or lengths by a common recognition mechanism. Sui L, Guo HC. Immunobiology 226 152112 (2021)
  10. The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I. Mavridis G, Mpakali A, Zoidakis J, Makridakis M, Vlahou A, Kaloumenou E, Ziotopoulou A, Georgiadis D, Papakyriakou A, Stratikos E. Sci Rep 11 16475 (2021)
  11. Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 spike glycoprotein. Stamatakis G, Samiotaki M, Temponeras I, Panayotou G, Stratikos E. J Biol Chem 297 101329 (2021)
  12. Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase. Temponeras I, Chiniadis L, Papakyriakou A, Stratikos E. Pharmaceuticals (Basel) 14 584 (2021)
  13. Functional ERAP1 Variants Distinctively Associate with Ankylosing Spondylitis Susceptibility under the Influence of HLA-B27 in Taiwanese. Wang CM, Liu MK, Jan Wu YJ, Lin JC, Zheng JW, Wu J, Chen JY. Cells 11 2427 (2022)
  14. Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus. Schott BH, Wang L, Zhu X, Harding AT, Ko ER, Bourgeois JS, Washington EJ, Burke TW, Anderson J, Bergstrom E, Gardener Z, Paterson S, Brennan RG, Chiu C, McClain MT, Woods CW, Gregory SG, Heaton NS, Ko DC. Cell Genom 2 100207 (2022)
  15. The ER Aminopeptidases, ERAP1 and ERAP2, synergize to self-modulate their respective activities. Martín-Esteban A, Rodriguez JC, Peske D, Lopez de Castro JA, Shastri N, Sadegh-Nasseri S. Front Immunol 13 1066483 (2022)
  16. Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1. Wilding B, Pasqua AE, E A Chessum N, Pierrat OA, Hahner T, Tomlin K, Shehu E, Burke R, Richards GM, Whitton B, Arwert EN, Thapaliya A, Salimraj R, van Montfort R, Skawinska A, Hayes A, Raynaud F, Chopra R, Jones K, Newton G, Cheeseman MD. Bioorg Med Chem Lett 42 128050 (2021)
  17. Structure of puromycin-sensitive aminopeptidase and polyglutamine binding. Madabushi S, Chow KM, Song ES, Goswami A, Hersh LB, Rodgers DW. PLoS One 18 e0287086 (2023)


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