Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we u...

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Autores principales:	Dheeraj Prakaash, Graham P Cook, Oreste Acuto, Antreas C Kalli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/eef43c7c0731423c8ca702ee06b2de21
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spelling	oai:doaj.org-article:eef43c7c0731423c8ca702ee06b2de212021-12-02T19:57:23ZMulti-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.1553-734X1553-735810.1371/journal.pcbi.1009232https://doaj.org/article/eef43c7c0731423c8ca702ee06b2de212021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009232https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation.Dheeraj PrakaashGraham P CookOreste AcutoAntreas C KalliPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 7, p e1009232 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Dheeraj Prakaash Graham P Cook Oreste Acuto Antreas C Kalli Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
description	The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation.
format	article
author	Dheeraj Prakaash Graham P Cook Oreste Acuto Antreas C Kalli
author_facet	Dheeraj Prakaash Graham P Cook Oreste Acuto Antreas C Kalli
author_sort	Dheeraj Prakaash
title	Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
title_short	Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
title_full	Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
title_fullStr	Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
title_full_unstemmed	Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
title_sort	multi-scale simulations of the t cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/eef43c7c0731423c8ca702ee06b2de21
work_keys_str_mv	AT dheerajprakaash multiscalesimulationsofthetcellreceptorrevealitslipidinteractionsdynamicsandthearrangementofitscytoplasmicregion AT grahampcook multiscalesimulationsofthetcellreceptorrevealitslipidinteractionsdynamicsandthearrangementofitscytoplasmicregion AT oresteacuto multiscalesimulationsofthetcellreceptorrevealitslipidinteractionsdynamicsandthearrangementofitscytoplasmicregion AT antreasckalli multiscalesimulationsofthetcellreceptorrevealitslipidinteractionsdynamicsandthearrangementofitscytoplasmicregion
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Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.

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