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Published online November 24, 2008
doi:10.1083/jcb.200804161
The Journal of Cell Biology, Vol. 183, No. 5, 865-879
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Frantz et al.
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Article

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



Christian Frantz1, Gabriela Barreiro2, Laura Dominguez2, Xiaoming Chen3, Robert Eddy3, John Condeelis3,4, Mark J.S. Kelly2, Matthew P. Jacobson2, and Diane L. Barber1

1 Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143
2 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158
3 Department of Anatomy and Structural Biology and 4 Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, NY 10461

Correspondence to Diane L. Barber: diane.barber{at}ucsf.edu

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 His133. 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.

Abbreviations used in this paper: ADF, actin-depolymerizing factor; HSQC, heteronuclear single quantum coherence; MD, molecular dynamics; NMR, nuclear magnetic resonance; pHi, intracellular pH; PI(4,5)P2, phosphotidylinositol-4,5-bisphosphate; PI3-kinase, phosphoinositide 3-kinase; WT, wild type.

© 2008 Frantz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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