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

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)

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

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

Grant/Contract Number:: AC02-98CH10886; SC0012704

OSTI ID:: 1875642

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

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

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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