Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism

Maben, Zachary; Arya, Richa; Georgiadis, Dimitris; Stratikos, Efstratios; Stern, Lawrence J.

doi:10.1038/s41467-021-25564-w

Title: Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism

Journal Article · Mon Sep 06 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-25564-w· OSTI ID:1875642

Maben, Zachary ^[1]; Arya, Richa ^[1]; Georgiadis, Dimitris ^[2];

^[2];

^[1]

Univ. of Massachusetts Medical School, Worcester, MA (United States)
Univ. of Athens (Greece)

The endoplasmic-reticulum aminopeptidase ERAP1 processes antigenic peptides for loading on MHC-I proteins and recognition by CD8 T cells as they survey the body for infection and malignancy. Crystal structures have revealed ERAP1 in either open or closed conformations, but whether these occur in solution and are involved in catalysis is not clear. Here, we assess ERAP1 conformational states in solution in the presence of substrates, allosteric activators, and inhibitors by small-angle X-ray scattering. We also characterize changes in protein conformation by X-ray crystallography, and we localize alternate C-terminal binding sites by chemical crosslinking. Structural and enzymatic data suggest that the structural reconfigurations of ERAP1 active site are physically linked to domain closure and are promoted by binding of long peptide substrates. These results clarify steps required for ERAP1 catalysis, demonstrate the importance of conformational dynamics within the catalytic cycle, and provide a mechanism for the observed allosteric regulation and Lys/Arg528 polymorphism disease association.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: SC0012704; AC02-98CH10886; KP1605010; S10 OD012331; AI153828; P30 GM124169; S10OD018483; P41 GM111244

OSTI ID:: 1875642

Report Number(s):: BNL-223140-2022-JACI

Journal Information:: Nature Communications, Vol. 12, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (62)

ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules Nagarajan, Niranjana A.; de Verteuil, Danielle A.; Sriranganadane, Dev The Journal of Immunology, Vol. 197, Issue 4 https://doi.org/10.4049/jimmunol.1500654	journal	August 2016
Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma Mehta, Akash M.; Jordanova, Ekaterina S.; Corver, Willem E. Genes, Chromosomes and Cancer, Vol. 48, Issue 5 https://doi.org/10.1002/gcc.20648	journal	May 2009
ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations Roberts, Amity R.; Appleton, Louise H.; Cortes, Adrian Proceedings of the National Academy of Sciences, Vol. 114, Issue 3 https://doi.org/10.1073/pnas.1618856114	journal	January 2017
Association of HLA-B27 and ERAP1 with ankylosing spondylitis susceptibility in Beijing Han Chinese Zhang, Z.; Dai, D.; Yu, K. Tissue Antigens, Vol. 83, Issue 5 https://doi.org/10.1111/tan.12334	journal	March 2014
Association of ankylosing spondylitis with HLA-B27 and ERAP1: Pathogenic role of antigenic peptide Chen, Bin; Li, Dahe; Xu, Weidong Medical Hypotheses, Vol. 80, Issue 1 https://doi.org/10.1016/j.mehy.2012.10.003	journal	January 2013
Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome Sanz-Bravo, Alejandro; Alvarez-Navarro, Carlos; Martín-Esteban, Adrian Molecular & Cellular Proteomics, Vol. 17, Issue 7 https://doi.org/10.1074/mcp.RA117.000565	journal	July 2018
Dominant Role of the ERAP1 Polymorphism R528K in Shaping the HLA-B27 Peptidome Through Differential Processing Determined by Multiple Peptide Residues Sanz-Bravo, Alejandro; Campos, José; Mazariegos, Marina S. Arthritis & Rheumatology, Vol. 67, Issue 3 https://doi.org/10.1002/art.38980	journal	February 2015
Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme Evnouchidou, Irini; Kamal, Ram P.; Seregin, Sergey S. The Journal of Immunology, Vol. 186, Issue 4 https://doi.org/10.4049/jimmunol.1003337	journal	January 2011
M1 aminopeptidases as drug targets: broad applications or therapeutic niche? Drinkwater, Nyssa; Lee, Jisook; Yang, Wei The FEBS Journal, Vol. 284, Issue 10 https://doi.org/10.1111/febs.14009	journal	February 2017
Hypothesis for a Neuronal Mechanism involved in Memory Fillenz, Marianne Nature, Vol. 238, Issue 5358 https://doi.org/10.1038/238041a0	journal	July 1972
Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming Kochan, G.; Krojer, T.; Harvey, D. Proceedings of the National Academy of Sciences, Vol. 108, Issue 19 https://doi.org/10.1073/pnas.1101262108	journal	April 2011
Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1 Nguyen, Tina T.; Chang, Shih-Chung; Evnouchidou, Irini Nature Structural & Molecular Biology, Vol. 18, Issue 5 https://doi.org/10.1038/nsmb.2021	journal	April 2011
Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl The Journal of Immunology, Vol. 195, Issue 6 https://doi.org/10.4049/jimmunol.1501103	journal	August 2015
Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides: Structure of Insulin-Regulated Aminopeptidase Hermans, Stefan J.; Ascher, David B.; Hancock, Nancy C. Protein Science, Vol. 24, Issue 2 https://doi.org/10.1002/pro.2604	journal	December 2014
Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl Journal of Medicinal Chemistry, Vol. 60, Issue 7 https://doi.org/10.1021/acs.jmedchem.6b01890	journal	April 2017
The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues York, Ian A.; Chang, Shih-Chung; Saric, Tomo Nature Immunology, Vol. 3, Issue 12 https://doi.org/10.1038/ni860	journal	November 2002
The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism Chang, S. -C.; Momburg, F.; Bhutani, N. Proceedings of the National Academy of Sciences, Vol. 102, Issue 47 https://doi.org/10.1073/pnas.0500721102	journal	November 2005
Effects of polymorphic variation on the mechanism of Endoplasmic Reticulum Aminopeptidase 1 Stamogiannos, Athanasios; Koumantou, Despoina; Papakyriakou, Athanasios Molecular Immunology, Vol. 67, Issue 2 https://doi.org/10.1016/j.molimm.2015.07.010	journal	October 2015
Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation Liddle, John; Hutchinson, Jonathan P.; Kitchen, Semra Journal of Medicinal Chemistry, Vol. 63, Issue 6 https://doi.org/10.1021/acs.jmedchem.9b02123	journal	February 2020
Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1 Maben, Zachary; Arya, Richa; Rane, Digamber Journal of Medicinal Chemistry, Vol. 63, Issue 1 https://doi.org/10.1021/acs.jmedchem.9b00293	journal	December 2019
Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1 Giastas, Petros; Mpakali, Anastasia; Papakyriakou, Athanasios Proceedings of the National Academy of Sciences, Vol. 116, Issue 52 https://doi.org/10.1073/pnas.1912070116	journal	December 2019
Crystal structure of a polypeptide’s C-terminus in complex with the regulatory domain of ER aminopeptidase 1 Sui, Lufei; Gandhi, Amit; Guo, Hwai-Chen Molecular Immunology, Vol. 80 https://doi.org/10.1016/j.molimm.2016.10.012	journal	December 2016
Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. Umezawa, Hamao; Aoyagi, Takaaki; Suda, Hiroyuki The Journal of Antibiotics, Vol. 29, Issue 1 https://doi.org/10.7164/antibiotics.29.97	journal	January 1976
L-Leucinthiol — A potent inhibitor of leucine aminopeptidase Chan, William W. -C. Biochemical and Biophysical Research Communications, Vol. 116, Issue 1 https://doi.org/10.1016/0006-291X(83)90414-X	journal	October 1983
The slow, tight binding of bestatin and amastatin to aminopeptidases. Wilkes, S. H.; Prescott, J. M. Journal of Biological Chemistry, Vol. 260, Issue 24 https://doi.org/10.1016/S0021-9258(17)38851-8	journal	October 1985
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance York, I. A.; Brehm, M. A.; Zendzian, S. Proceedings of the National Academy of Sciences, Vol. 103, Issue 24 https://doi.org/10.1073/pnas.0603095103	journal	June 2006
Solution scattering at the Life Science X-ray Scattering (LiX) beamline Yang, Lin; Antonelli, Stephen; Chodankar, Shirish Journal of Synchrotron Radiation, Vol. 27, Issue 3 https://doi.org/10.1107/S1600577520002362	journal	March 2020
Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1 Stamogiannos, Athanasios; Maben, Zachary; Papakyriakou, Athanasios Biochemistry, Vol. 56, Issue 10 https://doi.org/10.1021/acs.biochem.6b01170	journal	March 2017
Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses Zervoudi, Efthalia; Saridakis, Emmanuel; Birtley, James R. Proceedings of the National Academy of Sciences, Vol. 110, Issue 49 https://doi.org/10.1073/pnas.1309781110	journal	November 2013
High-Resolution Crystal Structure of Endoplasmic Reticulum Aminopeptidase 1 with Bound Phosphinic Transition-State Analogue Inhibitor Giastas, Petros; Neu, Margarete; Rowland, Paul ACS Medicinal Chemistry Letters, Vol. 10, Issue 5 https://doi.org/10.1021/acsmedchemlett.9b00002	journal	February 2019
Structure-Based Dissection of the Active Site Chemistry of Leukotriene A4 Hydrolase: Implications for M1 Aminopeptidases and Inhibitor Design Tholander, Fredrik; Muroya, Ayumo; Roques, Bernard-Pierre Chemistry & Biology, Vol. 15, Issue 9 https://doi.org/10.1016/j.chembiol.2008.07.018	journal	September 2008
A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1 Mavridis, George; Arya, Richa; Domnick, Alexander Journal of Biological Chemistry, Vol. 295, Issue 21 https://doi.org/10.1074/jbc.RA120.012976	journal	May 2020
p-Benzoyl-L-phenylalanine, a new photoreactive amino acid. Photolabeling of calmodulin with a synthetic calmodulin-binding peptide. Kauer, J. C.; Erickson-Viitanen, S.; Wolfe, H. R. Journal of Biological Chemistry, Vol. 261, Issue 23 https://doi.org/10.1016/S0021-9258(18)67441-1	journal	August 1986
Structural insights into the molecular ruler mechanism of the endoplasmic reticulum aminopeptidase ERAP1 Gandhi, Amit; Lakshminarasimhan, Damodharan; Sun, Yixin Scientific Reports, Vol. 1, Issue 1 https://doi.org/10.1038/srep00186	journal	December 2011
Structural basis for multifunctional roles of mammalian aminopeptidase N Chen, L.; Lin, Y. -L.; Peng, G. Proceedings of the National Academy of Sciences, Vol. 109, Issue 44 https://doi.org/10.1073/pnas.1210123109	journal	October 2012
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility Evans, David M.; Spencer, Chris C. A. Nature Genetics, Vol. 43, Issue 8 https://doi.org/10.1038/ng.873	journal	July 2011
Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals Bettencourt, B. F.; Rocha, F. L.; Alves, H. Rheumatology, Vol. 52, Issue 12 https://doi.org/10.1093/rheumatology/ket269	journal	September 2013
ERAP1Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis Costantino, Félicie; Talpin, Alice; Evnouchidou, Irini Arthritis & Rheumatology, Vol. 67, Issue 6 https://doi.org/10.1002/art.39072	journal	May 2015
Antigenic peptide trimming by ER aminopeptidases—Insights from structural studies Stratikos, Efstratios; Stern, Lawrence J. Molecular Immunology, Vol. 55, Issue 3-4 https://doi.org/10.1016/j.molimm.2013.03.002	journal	October 2013
Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1 Goto, Yoshikuni; Hattori, Akira; Ishii, Yasuhiro FEBS Letters, Vol. 580, Issue 7 https://doi.org/10.1016/j.febslet.2006.02.041	journal	February 2006
The Internal Sequence of the Peptide-Substrate Determines Its N-Terminus Trimming by ERAP1 Evnouchidou, Irini; Momburg, Frank; Papakyriakou, Athanasios PLoS ONE, Vol. 3, Issue 11 https://doi.org/10.1371/journal.pone.0003658	journal	November 2008
Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease Ombrello, Michael J.; Kastner, Daniel L.; Remmers, Elaine F. Current Opinion in Rheumatology, Vol. 27, Issue 4 https://doi.org/10.1097/BOR.0000000000000189	journal	July 2015
Structural Modeling Using Solution Small-Angle X-ray Scattering (SAXS) Gräwert, Tobias W.; Svergun, Dmitri I. Journal of Molecular Biology, Vol. 432, Issue 9 https://doi.org/10.1016/j.jmb.2020.01.030	journal	April 2020
Solid-phase Total Synthesis of (−)-Apratoxin A and Its Analogues and Their Biological Evaluation Doi, Takayuki; Numajiri, Yoshitaka; Takahashi, Takashi Chemistry - An Asian Journal, Vol. 6, Issue 1 https://doi.org/10.1002/asia.201000549	journal	November 2010
A convenient method to synthesize phosphinic peptides containing an aspartyl or glutamyl aminophosphinic acid. Use of the phenyl group as the carboxyl synthon Georgiadis, Dimitris; Matziari, Magdalini; Vassiliou, Stamatia Tetrahedron, Vol. 55, Issue 51 https://doi.org/10.1016/S0040-4020(99)00910-2	journal	December 1999
1-Aminoalkylphosphonous acids. Part 1. Isosteres of the protein amino acids Baylis, E. Keith; Campbell, Colin D.; Dingwall, John G. Journal of the Chemical Society, Perkin Transactions 1 https://doi.org/10.1039/p19840002845	journal	January 1984
Protection of the Hydroxyphosphinyl Function of Phosphinic Dipeptides by Adamantyl. Application to the Solid-Phase Synthesis of Phosphinic Peptides Yiotakis, Athanasios; Vassiliou, Stamatia; Jiráček, Jiří The Journal of Organic Chemistry, Vol. 61, Issue 19 https://doi.org/10.1021/jo9603439	journal	January 1996
FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A. Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw389	journal	May 2016
Structure-based model of allostery predicts coupling between distant sites Weinkam, P.; Pons, J.; Sali, A. Proceedings of the National Academy of Sciences, Vol. 109, Issue 13 https://doi.org/10.1073/pnas.1116274109	journal	March 2012
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Linking Crystallographic Model and Data Quality Karplus, P. A.; Diederichs, K. Science, Vol. 336, Issue 6084 https://doi.org/10.1126/science.1218231	journal	May 2012
Polder maps: improving OMIT maps by excluding bulk solvent Liebschner, Dorothee; Afonine, Pavel V.; Moriarty, Nigel W. Acta Crystallographica Section D Structural Biology, Vol. 73, Issue 2, p. 148-157 https://doi.org/10.1107/S2059798316018210	journal	February 2017
PRODRG : a tool for high-throughput crystallography of protein–ligand complexes Schüttelkopf, Alexander W.; van Aalten, Daan M. F. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 8 https://doi.org/10.1107/S0907444904011679	journal	July 2004
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
MolProbity: More and better reference data for improved all-atom structure validation: PROTEIN SCIENCE.ORG Williams, Christopher J.; Headd, Jeffrey J.; Moriarty, Nigel W. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3330	journal	November 2017
Macromolecular TLS Refinement in REFMAC at Moderate Resolutions Winn, Martyn D.; Murshudov, Garib N.; Papiz, Miroslav Z. Methods in Enzymology https://doi.org/10.1016/S0076-6879(03)74014-2	book	January 2003
Paired refinement under the control ofPAIREF Malý, Martin; Diederichs, Kay; Dohnálek, Jan IUCrJ, Vol. 7, Issue 4 https://doi.org/10.1107/S2052252520005916	journal	June 2020
PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations Dolinsky, T. J.; Nielsen, J. E.; McCammon, J. A. Nucleic Acids Research, Vol. 32, Issue Web Server, p. W665-W667 https://doi.org/10.1093/nar/gkh381	journal	July 2004
DelPhiForce web server: electrostatic forces and energy calculations and visualization Li, Lin; Jia, Zhe; Peng, Yunhui Bioinformatics, Vol. 33, Issue 22 https://doi.org/10.1093/bioinformatics/btx495	journal	August 2017

Similar Records

ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation

Journal Article · Thu Oct 10 00:00:00 EDT 2019 · Journal of Biological Chemistry · OSTI ID:1875642

Li, Lenong; Batliwala, Mansoor; Bouvier, Marlene

Structural Basis For Antigenic Peptide Precursor Processing by the Endoplasmic Reticulum Aminopeptidase ERAP1

Journal Article · Sat Dec 31 00:00:00 EST 2011 · Nature Structural and Molecular Biology · OSTI ID:1875642

Nguyen, T; Chang, S; Evnouchidou, I; +6 more

Conformational equilibria in allosteric control of Hsp70 chaperones

Journal Article · Fri Oct 01 00:00:00 EDT 2021 · Molecular Cell · OSTI ID:1875642

Wang, Wei; Liu, Qinglian; Liu, Qun; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
enzyme mechanisms
SAXS
x-ray crystallography

Title: Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism

Citation Formats

References (62)

Similar Records

Related Subjects