Journal of Molecular Modeling

, 25:277 | Cite as

The structural basis for membrane assembly of immunoreceptor signalling complexes

  • Namita Dube
  • Jan K. Marzinek
  • Robert C. Glen
  • Peter J. BondEmail author
Original Paper
Part of the following topical collections:
  1. Tim Clark 70th Birthday Festschrift


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.


Molecular dynamics (MD) simulation T cell receptor (TCR) Transmembrane domain Lipid bilayer ITAM motif 



We acknowledge access to the Darwin supercomputer of the University of Cambridge, and the HECToR UK supercomputer service for computational resources awarded by CCP-BioSim. ND thanks Maite Ortiz-Suarez and Mark Williamson for assistance during simulation analysis.

Funding information

This work received financial support from the Nehru Trust of the University of Cambridge and Rajiv Gandhi (UK) foundation. PJB and JKM acknowledge funding from the National Research Foundation (NRF2017NRF-CRP001-027).

Supplementary material

894_2019_4165_MOESM1_ESM.docx (3 mb)
ESM 1 (DOCX 3083 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Namita Dube
    • 1
    • 2
  • Jan K. Marzinek
    • 3
  • Robert C. Glen
    • 1
    • 4
  • Peter J. Bond
    • 3
    • 5
    Email author
  1. 1.Department of ChemistryUniversity of CambridgeCambridgeUK
  2. 2.Tata Institute of Fundamental ResearchHyderabadIndia
  3. 3.Bioinformatics Institute (A*STAR)SingaporeSingapore
  4. 4.Division of Integrative Systems Medicine and Digestive Diseases, Department of Surgery and CancerImperial College LondonLondonUK
  5. 5.Department of Biological SciencesNational University of SingaporeSingaporeSingapore

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