Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding

Christian Frantz, Gabriela Barreiro, Laura Dominguez, Xiaoming Chen, Robert J. Eddy, John S. Condeelis, Mark J S Kelly, Matthew P. Jacobson, Diane L. Barber

Research output: Contribution to journalArticle

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Abstract

Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H + efflux by the Na-H exchanger NHE1. The first phase is restored by expression of mutant cofilin-H133A but not unphosphorylated cofilin-S3A. Constant pH molecular dynamics simulations and nuclear magnetic resonance (NMR) reveal pH-sensitive structural changes in the cofilin C-terminal filamentous actin binding site dependent on His1 33. However, cofilin-H133A retains pH-sensitive changes in NMR spectra and severing activity in vitro, which suggests that it has a more complex behavior in cells. Cofilin activity is inhibited by phosphoinositide binding, and we found that phosphoinositide binding is pH-dependent for wild-type cofilin, with decreased binding at a higher pH. In contrast, phosphoinositide binding by cofilin-H133A is attenuated and pH insensitive. These data suggest a molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics.

Original languageEnglish (US)
Pages (from-to)865-879
Number of pages15
JournalJournal of Cell Biology
Volume183
Issue number5
DOIs
StatePublished - Dec 1 2008

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Actin Depolymerizing Factors
Phosphatidylinositols
Actins
Actin Cytoskeleton
Magnetic Resonance Spectroscopy
Sodium-Hydrogen Antiporter
Molecular Dynamics Simulation
Intercellular Signaling Peptides and Proteins
Fibroblasts
Binding Sites
Membranes

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

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Cofilin is a pH sensor for actin free barbed end formation : role of phosphoinositide binding. / Frantz, Christian; Barreiro, Gabriela; Dominguez, Laura; Chen, Xiaoming; Eddy, Robert J.; Condeelis, John S.; Kelly, Mark J S; Jacobson, Matthew P.; Barber, Diane L.

In: Journal of Cell Biology, Vol. 183, No. 5, 01.12.2008, p. 865-879.

Research output: Contribution to journalArticle

Frantz, C, Barreiro, G, Dominguez, L, Chen, X, Eddy, RJ, Condeelis, JS, Kelly, MJS, Jacobson, MP & Barber, DL 2008, 'Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding', Journal of Cell Biology, vol. 183, no. 5, pp. 865-879. https://doi.org/10.1083/jcb.200804161
Frantz, Christian ; Barreiro, Gabriela ; Dominguez, Laura ; Chen, Xiaoming ; Eddy, Robert J. ; Condeelis, John S. ; Kelly, Mark J S ; Jacobson, Matthew P. ; Barber, Diane L. / Cofilin is a pH sensor for actin free barbed end formation : role of phosphoinositide binding. In: Journal of Cell Biology. 2008 ; Vol. 183, No. 5. pp. 865-879.
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