How multisite phosphorylation impacts the conformations of intrinsically disordered proteins.

Abstract:

Phosphorylation of intrinsically disordered proteins (IDPs) can produce changes in structural and dynamical properties and thereby mediate critical biological functions. How phosphorylation effects intrinsically disordered proteins has been studied for an increasing number of IDPs, but a systematic understanding is still lacking. Here, we compare the collapse propensity of four disordered proteins, Ash1, the C-terminal domain of RNA polymerase (CTD2'), the cytosolic domain of E-Cadherin, and a fragment of the p130Cas, in unphosphorylated and phosphorylated forms using extensive all-atom molecular dynamics (MD) simulations. We find all proteins to show V-shape changes in their collapse propensity upon multi-site phosphorylation according to their initial net charge: phosphorylation expands neutral or overall negatively charged IDPs and shrinks positively charged IDPs. However, force fields including those tailored towards and commonly used for IDPs overestimate these changes. We find quantitative agreement of MD results with SAXS and NMR data for Ash1 and CTD2' only when attenuating protein electrostatic interactions by using a higher salt concentration (e.g. 350 mM), highlighting the overstabilization of salt bridges in current force fields. We show that phosphorylation of IDPs also has a strong impact on the solvation of the protein, a factor that in addition to the actual collapse or expansion of the IDP should be considered when analyzing SAXS data. Compared to the overall mild change in global IDP dimension, the exposure of active sites can change significantly upon phosphorylation, underlining the large susceptibility of IDP ensembles to regulation through post-translational modifications.

SEEK ID: https://publications.h-its.org/publications/1294

PubMed ID: 33945530

DOI: 10.1371/journal.pcbi.1008939

Research Groups: Molecular Biomechanics

Publication type: Journal

Journal: PLoS Computational Biology

Citation: PLoS Computational Biology,17(5):e1008939

Date Published: 4th May 2021

URL:

Registered Mode: manually

help Submitter
Citation
Jin, F., & Gräter, F. (2021). How multisite phosphorylation impacts the conformations of intrinsically disordered proteins. In A. MacKerell (Ed.), PLOS Computational Biology (Vol. 17, Issue 5, p. e1008939). Public Library of Science (PLoS). https://doi.org/10.1371/journal.pcbi.1008939
Activity

Views: 3220

Created: 27th Oct 2021 at 05:39

Last updated: 5th Mar 2024 at 21:24

help Tags

This item has not yet been tagged.

help Attributions

None

Powered by
(v.1.14.2)
Copyright © 2008 - 2023 The University of Manchester and HITS gGmbH