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

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 . However, no established structure determination method is currently available that can p...

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Bibliographic Details
Published in:	Journal of the American Chemical Society Vol. 143; no. 39; p. 16055
Main Authors:	Born, Alexandra, Soetbeer, Janne, Breitgoff, Frauke, Henen, Morkos A, Sgourakis, Nikolaos, Polyhach, Yevhen, Nichols, Parker J, Strotz, Dean, Jeschke, Gunnar, Vögeli, Beat
Format:	Journal Article
Language:	English
Published:	United States 06.10.2021
Subjects:	Humans Magnetic Resonance Spectroscopy - methods Models, Molecular Molecular Dynamics Simulation NIMA-Interacting Peptidylprolyl Isomerase - chemistry Nitric Oxide Synthase Type III - chemistry Nitric Oxide Synthase Type III - metabolism Protein Conformation
ISSN:	1520-5126, 1520-5126
Online Access:	Get more information
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Summary:	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 . 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), 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1520-5126 1520-5126
DOI:	10.1021/jacs.1c06289