Membrane-mediated dimerization potentiates PIP5K lipid kinase activity

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Abstract

The phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family of lipid modifying enzymes generate the majority of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) lipids found at the plasma membrane in eukaryotic cells. PI(4,5)P₂ lipids serve a critical role in regulating receptor activation, ion channel gating, endocytosis, and actin nucleation. Here we describe how PIP5K activity is regulated by cooperative binding to PI(4,5)P₂ lipids and membrane-mediated dimerization of the kinase domain. In contrast to constitutively dimeric phosphatidylinositol 5-phosphate 4-kinase (PIP4K, type II PIPK), solution PIP5K exists in a weak monomer-dimer equilibrium. PIP5K monomers can associate with PI(4,5)P₂ containing membranes and dimerize in a protein density dependent manner. Although dispensable for cooperative PI(4,5)P₂ binding, dimerization enhances the catalytic efficiency of PIP5K through a mechanism consistent with allosteric regulation. Additionally, dimerization amplifies stochastic variation in the kinase reaction velocity and strengthens effects such as the recently described stochastic geometry sensing. Overall, the mechanism of PIP5K membrane binding creates a broad dynamic range of lipid kinase activities that are coupled to the density of PI(4,5)P₂ and membrane bound kinase.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.

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Scott D Hansen

Department of Chemistry and Biochemistry, University of Oregon, Eugene, United States

For correspondence
shansen5@uoregon.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7005-6200
Albert A Lee

Department of Chemistry, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Benjamin R Duewell

Department of Chemistry and Biochemistry, University of Oregon, Eugene, United States

Competing interests
The authors declare that no competing interests exist.
Jay T Groves

Department of Chemistry, University of California, Berkeley, Berkeley, United States

For correspondence
JTGroves@lbl.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3037-5220

Funding

National Science Foundation (CAREER MCB-2048060)

Scott D Hansen

University of Oregon, Department of Chemistry and Biochemistry (lab startup funds)

Scott D Hansen

Novo Nordisk Foundation Challenge Programme (Center for Geometrically Engineered Cellular Systems)

Albert A Lee
Jay T Groves

National Institute of Health, NIGMS (National Research Service Award (NRSA),F32 GM111010-02)

Scott D Hansen

National Institute of Health, NIGMS (T32 GM007759)

Benjamin R Duewell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.