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How multisite phosphorylation impacts the conformations of intrinsically disordered proteins

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...

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Detalles Bibliográficos
Autores principales: Jin, Fan, Gräter, Frauke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148376/
https://www.ncbi.nlm.nih.gov/pubmed/33945530
http://dx.doi.org/10.1371/journal.pcbi.1008939
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author Jin, Fan
Gräter, Frauke
author_facet Jin, Fan
Gräter, Frauke
author_sort Jin, Fan
collection PubMed
description 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.
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spelling pubmed-81483762021-06-07 How multisite phosphorylation impacts the conformations of intrinsically disordered proteins Jin, Fan Gräter, Frauke PLoS Comput Biol Research Article 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. Public Library of Science 2021-05-04 /pmc/articles/PMC8148376/ /pubmed/33945530 http://dx.doi.org/10.1371/journal.pcbi.1008939 Text en © 2021 Jin, Gräter https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jin, Fan
Gräter, Frauke
How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title_full How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title_fullStr How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title_full_unstemmed How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title_short How multisite phosphorylation impacts the conformations of intrinsically disordered proteins
title_sort how multisite phosphorylation impacts the conformations of intrinsically disordered proteins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148376/
https://www.ncbi.nlm.nih.gov/pubmed/33945530
http://dx.doi.org/10.1371/journal.pcbi.1008939
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