Cholesterol-Dependent Phase-Demixing in Lipid Bilayers as a Switch for the Activity of the Phosphoinositide-Binding Cytoskeletal Protein Gelsolin

Yu Hsiu Wang, Robert Bucki, Paul A. Janmey

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The lateral distribution of phosphatidylinositol 4,5-bisphosphate (PIP2) in lipid bilayers is affected both by divalent cation-mediated attractions and cholesterol-dependent phase demixing. The effects of lateral redistribution of PIP2 within a membrane on PIP2-protein interactions are explored with an N-terminal fragment of gelsolin (NtGSN) that severs actin in a Ca2+-insensitive manner. The extent of NtGSN inhibition by PIP2-containing large unilamellar vesicles (LUVs) depends on the lateral organization of the membrane as quantified by an actin-severing assay. At a fixed PIP2 mole fraction, the inhibition is largely enhanced by the segregation of liquid ordered/liquid disordered (Lo/Ld) phases that is induced by altering either cholesterol content or temperature, whereas the presence of Ca2+ only slightly improves the inhibition. Inhibition of gelsolin induced by demixed LUVs is more effective with decreasing temperature, coincident with increasing membrane order as determined by Laurdan generalized polarization and is reversible as the temperature increases. This result suggests that PIP2-mediated inhibition of gelsolin function depends not only on changes in global concentration but also on lateral distribution of PIP2. These observations imply that gelsolin, and perhaps other PIP2-regulated proteins, can be activated or inactivated by the formation of nanodomains or clusters without changing PIP2 bulk concentration in the cell membrane.

Original languageEnglish (US)
Pages (from-to)3361-3369
Number of pages9
JournalBiochemistry
Volume55
Issue number24
DOIs
StatePublished - Jun 21 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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