Imperial College London
Alternate

ProfessorRobertGlen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Computational Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7912r.glen Website

 
 
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Location

 

362Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Dube:2019:10.1007/s00894-019-4165-6,
author = {Dube, N and Marzinek, JK and Glen, RC and Bond, PJ},
doi = {10.1007/s00894-019-4165-6},
journal = {Journal of Molecular Modeling},
pages = {1--14},
title = {The structural basis for membrane assembly of immunoreceptor signalling complexes},
url = {http://dx.doi.org/10.1007/s00894-019-4165-6},
volume = {25},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Immunoreceptors are TM complexes that consist of separate ligand-binding and signal-transducing modules. Mounting evidence suggests that interactions with the local environment may influence the architecture of these TM domains, which assemble via crucial sets of conserved ionisable residues, and also control the peripheral association of immunoreceptor tyrosine-based activation motifs (ITAMs) whose phosphorylation triggers cytoplasmic signalling cascades. We now report a molecular dynamics (MD) simulation study of the archetypal T cell receptor (TCR) and its cluster of differentiation 3 (CD3) signalling partners, along with the analogous DNAX-activation protein of 12 kDa (DAP12)/natural killer group 2C (NKG2C) complex. Based on > 15 μs of explicitly solvated, atomic-resolution sampling, we explore molecular aspects of immunoreceptor complex stability in different functionally relevant states. A novel alchemical approach is used to simulate the cytoplasmic CD3ε tail at different depths within lipid bilayer models, revealing that the conformation and cytoplasmic exposure of ITAMs are highly sensitive to local enrichment by different lipid species and to phosphorylation. Furthermore, simulations of the TCR and DAP12 TM domains in various states of oligomerisation suggest that, during the early stages of assembly, stable membrane insertion is facilitated by the interfacial lipid/solvent environment and/or partial ionisation of charged residues. Collectively, our results indicate that the architecture and mechanisms of signal transduction in immunoreceptor complexes are tightly regulated by interactions with the microenvironment.
AU  - Dube,N
AU  - Marzinek,JK
AU  - Glen,RC
AU  - Bond,PJ
DO  - 10.1007/s00894-019-4165-6
EP  - 14
PY  - 2019///
SN  - 0948-5023
SP  - 1
TI  - The structural basis for membrane assembly of immunoreceptor signalling complexes
T2  - Journal of Molecular Modeling
UR  - http://dx.doi.org/10.1007/s00894-019-4165-6
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000486490200002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://link.springer.com/article/10.1007%2Fs00894-019-4165-6
UR  - http://hdl.handle.net/10044/1/85330
VL  - 25
ER  -
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