Structure
Volume 27, Issue 8, 6 August 2019, Pages 1336-1346.e2
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Theory
Membrane Recognition and Binding by the Phosphatidylinositol Phosphate Kinase PIP5K1A: A Multiscale Simulation Study

https://doi.org/10.1016/j.str.2019.05.004Get rights and content
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Highlights

  • PIP5K1A kinase interacts with PIP-containing membranes via its activation loop

  • PIP5K1A does not bind to zwitterionic or anionic membranes lacking PIP molecules

  • Initial encounter of protein and bilayer is followed by reorientation and binding

  • Dimeric PIP5K1A binds with membrane contacts via only one catalytic site at a time

Summary

Phosphatidylinositol phosphates (PIPs) are lipid signaling molecules that play key roles in many cellular processes. PIP5K1A kinase catalyzes phosphorylation of PI4P to form PIP2, which in turn interacts with membrane and membrane-associated proteins. We explore the mechanism of membrane binding by the PIP5K1A kinase using a multiscale molecular dynamics approach. Coarse-grained simulations show binding of monomeric PIP5K1A to a model cell membrane containing PI4P. PIP5K1A did not bind to zwitterionic or anionic membranes lacking PIP molecules. Initial encounter of kinase and bilayer was followed by reorientation to enable productive binding to the PI4P-containing membrane. The simulations suggest that unstructured regions may be important for the preferred orientation for membrane binding. Atomistic simulations indicated that the dimeric kinase could not bind to the membrane via both active sites at the same time, suggesting a conformational change in the protein and/or bilayer distortion may be needed for dual-site binding to occur.

keywords

lipid kinase
MD simulations
membranes
phosphatidylinositol phosphate

Cited by (0)

3

Present address: Leeds Institute of Medical Research at St James's, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK

4

Lead Contact