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Reconstruction of Coupled Intra- and Interdomain Protein Motion from Nuclear and Electron Magnetic Resonance.

Authors :
Born A
Soetbeer J
Breitgoff F
Henen MA
Sgourakis N
Polyhach Y
Nichols PJ
Strotz D
Jeschke G
Vögeli B
Source :
Journal of the American Chemical Society [J Am Chem Soc] 2021 Oct 06; Vol. 143 (39), pp. 16055-16067. Date of Electronic Publication: 2021 Sep 27.
Publication Year :
2021

Abstract

Proteins composed of multiple domains allow for structural heterogeneity and interdomain dynamics that may be vital for function. Intradomain structures and dynamics can influence interdomain conformations and vice versa . However, no established structure determination method is currently available that can probe the coupling of these motions. The protein Pin1 contains separate regulatory and catalytic domains that sample "extended" and "compact" states, and ligand binding changes this equilibrium. Ligand binding and interdomain distance have been shown to impact the activity of Pin1, suggesting interdomain allostery. In order to characterize the conformational equilibrium of Pin1, we describe a novel method to model the coupling between intra- and interdomain dynamics at atomic resolution using multistate ensembles. The method uses time-averaged nuclear magnetic resonance (NMR) restraints and double electron-electron resonance (DEER) data that resolve distance distributions. While the intradomain calculation is primarily driven by exact nuclear Overhauser enhancements (eNOEs), J couplings, and residual dipolar couplings (RDCs), the relative domain distribution is driven by paramagnetic relaxation enhancement (PREs), RDCs, interdomain NOEs, and DEER. Our data support a 70:30 population of the compact and extended states in apo Pin1. A multistate ensemble describes these conformations simultaneously, with distinct conformational differences located in the interdomain interface stabilizing the compact or extended states. We also describe correlated conformations between the catalytic site and interdomain interface that may explain allostery driven by interdomain contact.

Details

Language :
English
ISSN :
1520-5126
Volume :
143
Issue :
39
Database :
MEDLINE
Journal :
Journal of the American Chemical Society
Publication Type :
Academic Journal
Accession number :
34579531
Full Text :
https://doi.org/10.1021/jacs.1c06289