The juxtamembrane regions of human receptor tyrosine kinases exhibit conserved interaction sites with anionic lipids

Scientific Reports
George HedgerHeidi Koldsø

Abstract

Receptor tyrosine kinases (RTKs) play a critical role in diverse cellular processes and their activity is regulated by lipids in the surrounding membrane, including PIP2 (phosphatidylinositol-4,5-bisphosphate) in the inner leaflet, and GM3 (monosialodihexosylganglioside) in the outer leaflet. However, the precise details of the interactions at the molecular level remain to be fully characterised. Using a multiscale molecular dynamics simulation approach, we comprehensively characterise anionic lipid interactions with all 58 known human RTKs. Our results demonstrate that the juxtamembrane (JM) regions of RTKs are critical for inducing clustering of anionic lipids, including PIP2, both in simple asymmetric bilayers, and in more complex mixed membranes. Clustering is predominantly driven by interactions between a conserved cluster of basic residues within the first five positions of the JM region, and negatively charged lipid headgroups. This highlights a conserved interaction pattern shared across the human RTK family. In particular predominantly the N-terminal residues of the JM region are involved in the interactions with PIP2, whilst residues within the distal JM region exhibit comparatively less lipid specificity. Our results...Continue Reading

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Citations

Feb 20, 2016·Current Opinion in Cell Biology·Marielle S KöberlinGiulio Superti-Furga
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Methods Mentioned

BETA
X-ray
NMR
FRET

Software Mentioned

ALINE
PSIPRED
JPRED
VMD
PyMOL ( PyMOL Molecular Graphics System
CryoEM
martinize
PyMOL
TMpred
GROMACS

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