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Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases

We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. Here we show that conformational pl...

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Autores principales: Araya, Mussie K., Gorfe, Alemayehu A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622456/
https://www.ncbi.nlm.nih.gov/pubmed/37919400
http://dx.doi.org/10.1038/s42003-023-05487-6
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author Araya, Mussie K.
Gorfe, Alemayehu A.
author_facet Araya, Mussie K.
Gorfe, Alemayehu A.
author_sort Araya, Mussie K.
collection PubMed
description We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. Here we show that conformational plasticity is a key determinant of lipid sorting by polybasic PIDRs and provide evidence for lipid sorting based on both headgroup and acyl chain structures. We further show that conformational ensemble-based lipid recognition is generalizable to all polybasic PIDRs, and that the sequence outside the polybasic domain (PBD) modulates the conformational plasticity, bilayer adsorption, and interactions of PIDRs with membrane lipids. Specifically, we find that palmitoylation, the ratio of basic to acidic residues, and the hydrophobic content of the sequence outside the PBD significantly impact the diversity of conformational substates and hence the extent of conformation-dependent lipid interactions. We thus propose that the PBD is required but not sufficient for the full realization of lipid sorting by prenylated PBD-containing membrane anchors, and that the membrane anchor is not only responsible for high affinity membrane binding but also directs the protein to the right target membrane where it participates in lipid sorting.
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spelling pubmed-106224562023-11-04 Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases Araya, Mussie K. Gorfe, Alemayehu A. Commun Biol Article We studied diverse prenylated intrinsically disordered regions (PIDRs) of Ras and Rho family small GTPases using long timescale atomistic molecular dynamics simulations in an asymmetric model membrane of phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. Here we show that conformational plasticity is a key determinant of lipid sorting by polybasic PIDRs and provide evidence for lipid sorting based on both headgroup and acyl chain structures. We further show that conformational ensemble-based lipid recognition is generalizable to all polybasic PIDRs, and that the sequence outside the polybasic domain (PBD) modulates the conformational plasticity, bilayer adsorption, and interactions of PIDRs with membrane lipids. Specifically, we find that palmitoylation, the ratio of basic to acidic residues, and the hydrophobic content of the sequence outside the PBD significantly impact the diversity of conformational substates and hence the extent of conformation-dependent lipid interactions. We thus propose that the PBD is required but not sufficient for the full realization of lipid sorting by prenylated PBD-containing membrane anchors, and that the membrane anchor is not only responsible for high affinity membrane binding but also directs the protein to the right target membrane where it participates in lipid sorting. Nature Publishing Group UK 2023-11-02 /pmc/articles/PMC10622456/ /pubmed/37919400 http://dx.doi.org/10.1038/s42003-023-05487-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Araya, Mussie K.
Gorfe, Alemayehu A.
Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title_full Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title_fullStr Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title_full_unstemmed Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title_short Conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small GTPases
title_sort conformational ensemble-dependent lipid recognition and segregation by prenylated intrinsically disordered regions in small gtpases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622456/
https://www.ncbi.nlm.nih.gov/pubmed/37919400
http://dx.doi.org/10.1038/s42003-023-05487-6
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AT gorfealemayehua conformationalensembledependentlipidrecognitionandsegregationbyprenylatedintrinsicallydisorderedregionsinsmallgtpases