Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism
Abstract
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.
- Authors:
-
[2];
[1]
- Univ. of Massachusetts Medical School, Worcester, MA (United States)
- Univ. of Athens (Greece)
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- OSTI Identifier:
- 1875642
- Report Number(s):
- BNL-223140-2022-JACI
Journal ID: ISSN 2041-1723
- Grant/Contract Number:
- SC0012704; AC02-98CH10886; KP1605010; S10 OD012331; AI153828; P30 GM124169; S10OD018483; P41 GM111244
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; enzyme mechanisms; SAXS; x-ray crystallography
Citation Formats
Maben, Zachary, Arya, Richa, Georgiadis, Dimitris, Stratikos, Efstratios, and Stern, Lawrence J. Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. United States: N. p., 2021.
Web. doi:10.1038/s41467-021-25564-w.
Maben, Zachary, Arya, Richa, Georgiadis, Dimitris, Stratikos, Efstratios, & Stern, Lawrence J. Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism. United States. https://doi.org/10.1038/s41467-021-25564-w
Maben, Zachary, Arya, Richa, Georgiadis, Dimitris, Stratikos, Efstratios, and Stern, Lawrence J. Mon .
"Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism". United States. https://doi.org/10.1038/s41467-021-25564-w. https://www.osti.gov/servlets/purl/1875642.
@article{osti_1875642,
title = {Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism},
author = {Maben, Zachary and Arya, Richa and Georgiadis, Dimitris and Stratikos, Efstratios and Stern, Lawrence J.},
abstractNote = {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.},
doi = {10.1038/s41467-021-25564-w},
journal = {Nature Communications},
number = 1,
volume = 12,
place = {United States},
year = {Mon Sep 06 00:00:00 EDT 2021},
month = {Mon Sep 06 00:00:00 EDT 2021}
}
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