The structural basis for membrane assembly of immunoreceptor signalling complexes
File(s)
Accepted version
Author(s)
Dube, Namita
Marzinek, Jan K
Glen, Robert C
Bond, Peter J
Type
Journal Article
Abstract
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.
Date Issued
2019-09-01
Date Acceptance
2019-08-15
Citation
Journal of Molecular Modeling, 2019, 25 (9), pp.1-14
ISSN
0948-5023
Publisher
Springer
Start Page
1
End Page
14
Journal / Book Title
Journal of Molecular Modeling
Volume
25
Issue
9
Copyright Statement
© 2019 Springer-Verlag. The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs00894-019-4165-6
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000486490200002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Technology
Biochemistry & Molecular Biology
Biophysics
Chemistry, Multidisciplinary
Computer Science, Interdisciplinary Applications
Chemistry
Computer Science
Molecular dynamics (MD) simulation
T cell receptor (TCR)
Transmembrane domain
Lipid bilayer
ITAM motif
T-CELL-RECEPTOR
ZETA-TRANSMEMBRANE DIMER
ACID SIDE-CHAINS
PROTEIN-STRUCTURE
SUBUNIT CONTAINS
CYTOPLASMIC TAIL
BINDING MOTIF
LIPID-BILAYER
FORCE-FIELD
CHARMM
Publication Status
Published
Article Number
ARTN 277
Date Publish Online
2019-08-27