PT  - JOURNAL ARTICLE
AU  - Dheeraj Prakaash
AU  - Graham P. Cook
AU  - Oreste Acuto
AU  - Antreas C. Kalli
TI  - Molecular dynamics simulations reveal membrane lipid interactions of the full-length lymphocyte specific kinase Lck
AID  - 10.1101/2022.05.10.491278
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.10.491278
4099  - http://biorxiv.org/content/early/2022/05/11/2022.05.10.491278.short
4100  - http://biorxiv.org/content/early/2022/05/11/2022.05.10.491278.full
AB  - The membrane-bound lymphocyte-specific protein-tyrosine kinase (Lck) triggers T cell antigen receptor signalling to initiate adaptive immune responses. Despite many structure-function studies, the mode of action of Lck and the potential role of plasma membrane lipids in regulating Lck’s activity remains elusive. Advances in molecular dynamics simulations of membrane proteins in complex lipid bilayers have opened a new perspective in gathering such information. Here, we have modelled the full-length Lck open and closed conformations available from crystallographic studies and simulated its interaction with the inner leaflet of the T cell plasma membrane. In both conformations, we found that the unstructured unique domain and the structured domains including the kinase interacted with the membrane with a preference for PIP lipids. Interestingly, our simulations suggest that the Lck-SH2 domain interacts with lipids differently in the open and closed Lck conformations, demonstrating that lipid interaction can potentially regulate Lck’s conformation and in turn modulate T cell signalling. Additionally, the Lck-SH2 and kinase domain residues that significantly contacted PIP lipids are found to be conserved among the Src family of kinases, thereby potentially representing similar PIP interactions within the family.Competing Interest StatementThe authors have declared no competing interest.