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Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains

Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate...

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Detalles Bibliográficos
Autores principales: Lumb, Craig N., Sansom, Mark S. P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406000/
https://www.ncbi.nlm.nih.gov/pubmed/22844242
http://dx.doi.org/10.1371/journal.pcbi.1002617
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author Lumb, Craig N.
Sansom, Mark S. P.
author_facet Lumb, Craig N.
Sansom, Mark S. P.
author_sort Lumb, Craig N.
collection PubMed
description Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P(3)). The interaction of GRP1-PH with PI(3,4,5)P(3) in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic ‘decoy’ lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)P(3)-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as ‘decoys’, disrupting the interaction of GRP1-PH with the PI(3,4,5)P(3) molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)P(3) within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)P(3), forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation.
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spelling pubmed-34060002012-07-27 Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains Lumb, Craig N. Sansom, Mark S. P. PLoS Comput Biol Research Article Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P(3)). The interaction of GRP1-PH with PI(3,4,5)P(3) in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic ‘decoy’ lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)P(3)-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as ‘decoys’, disrupting the interaction of GRP1-PH with the PI(3,4,5)P(3) molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)P(3) within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)P(3), forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation. Public Library of Science 2012-07-26 /pmc/articles/PMC3406000/ /pubmed/22844242 http://dx.doi.org/10.1371/journal.pcbi.1002617 Text en Lumb, Sansom. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lumb, Craig N.
Sansom, Mark S. P.
Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title_full Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title_fullStr Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title_full_unstemmed Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title_short Finding a Needle in a Haystack: The Role of Electrostatics in Target Lipid Recognition by PH Domains
title_sort finding a needle in a haystack: the role of electrostatics in target lipid recognition by ph domains
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406000/
https://www.ncbi.nlm.nih.gov/pubmed/22844242
http://dx.doi.org/10.1371/journal.pcbi.1002617
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