Assessing the relative stability of dimer interfaces in g protein-coupled receptors.

Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debat...

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Autores principales:	Jennifer M Johnston, Hao Wang, Davide Provasi, Marta Filizola
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d1aa65b26ff0413295a1c2794abcfbff
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spelling	oai:doaj.org-article:d1aa65b26ff0413295a1c2794abcfbff2021-11-18T05:51:05ZAssessing the relative stability of dimer interfaces in g protein-coupled receptors.1553-734X1553-735810.1371/journal.pcbi.1002649https://doaj.org/article/d1aa65b26ff0413295a1c2794abcfbff2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22916005/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debate. Motivated by experimental data suggesting differing stabilities for homomers of the cognate human β1- and β2-adrenergic receptors, we have carried out approximately 160 microseconds of biased molecular dynamics simulations to calculate the dimerization free energy of crystal structure-based models of these receptors, interacting at two interfaces that have often been implicated in GPCR association under physiological conditions. Specifically, results are presented for simulations of coarse-grained (MARTINI-based) and atomistic representations of each receptor, in homodimeric configurations with either transmembrane helices TM1/H8 or TM4/3 at the interface, in an explicit lipid bilayer. Our results support a definite contribution to the relative stability of GPCR dimers from both interface sequence and configuration. We conclude that β1- and β2-adrenergic receptor homodimers with TM1/H8 at the interface are more stable than those involving TM4/3, and that this might be reconciled with experimental studies by considering a model of oligomerization in which more stable TM1 homodimers diffuse through the membrane, transiently interacting with other protomers at interfaces involving other TM helices.Jennifer M JohnstonHao WangDavide ProvasiMarta FilizolaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 8, p e1002649 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jennifer M Johnston Hao Wang Davide Provasi Marta Filizola Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
description	Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate in the plasma membrane to form homo- and/or heteromers. Nevertheless, the stoichiometry, fraction and lifetime of such receptor complexes in living cells remain topics of intense debate. Motivated by experimental data suggesting differing stabilities for homomers of the cognate human β1- and β2-adrenergic receptors, we have carried out approximately 160 microseconds of biased molecular dynamics simulations to calculate the dimerization free energy of crystal structure-based models of these receptors, interacting at two interfaces that have often been implicated in GPCR association under physiological conditions. Specifically, results are presented for simulations of coarse-grained (MARTINI-based) and atomistic representations of each receptor, in homodimeric configurations with either transmembrane helices TM1/H8 or TM4/3 at the interface, in an explicit lipid bilayer. Our results support a definite contribution to the relative stability of GPCR dimers from both interface sequence and configuration. We conclude that β1- and β2-adrenergic receptor homodimers with TM1/H8 at the interface are more stable than those involving TM4/3, and that this might be reconciled with experimental studies by considering a model of oligomerization in which more stable TM1 homodimers diffuse through the membrane, transiently interacting with other protomers at interfaces involving other TM helices.
format	article
author	Jennifer M Johnston Hao Wang Davide Provasi Marta Filizola
author_facet	Jennifer M Johnston Hao Wang Davide Provasi Marta Filizola
author_sort	Jennifer M Johnston
title	Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
title_short	Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
title_full	Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
title_fullStr	Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
title_full_unstemmed	Assessing the relative stability of dimer interfaces in g protein-coupled receptors.
title_sort	assessing the relative stability of dimer interfaces in g protein-coupled receptors.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/d1aa65b26ff0413295a1c2794abcfbff
work_keys_str_mv	AT jennifermjohnston assessingtherelativestabilityofdimerinterfacesingproteincoupledreceptors AT haowang assessingtherelativestabilityofdimerinterfacesingproteincoupledreceptors AT davideprovasi assessingtherelativestabilityofdimerinterfacesingproteincoupledreceptors AT martafilizola assessingtherelativestabilityofdimerinterfacesingproteincoupledreceptors
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Assessing the relative stability of dimer interfaces in g protein-coupled receptors.

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