Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF, 1107K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sedwick, C. Search for Related Content PubMed Articles by Sedwick, C. Social Bookmarking                            What's this?

Cofilin activity is a total coincidence

Deprotonation at His133 releases PI(4,5)P2 from cofilin.

Frantz et al. demonstrate how events coincide at the cell's leading edge to regulate the activity of actin-severing cofilin.

Cofilin promotes the formation of actin filaments at the front of motile cells by binding to existing filaments and cutting them, creating barbed ends for new filament nucleation. Cofilin activation requires Ser3 dephosphorylation; however, this alone is not sufficient. Additional mechanisms—including deprotonation of His133 (by increasing cellular pH), and release from membrane phospholipid, PI(4,5)P2—might also be necessary. Cofilin presumably acts as a "coincidence detector" for these signals, explains author Diane Barber.

The question was, how do these individual regulatory events combine. Increased pH by H+ efflux had been suggested for the His133 deprotonation, and the authors now confirm that, in response to migratory cues, H+ efflux by the mammalian Na-H exchanger (NHE1) was required for increasing actin barbed end formation by cofilin. As for PI(4,5)P2 release, the authors found that His133 deprotonation in fact decreased cofilin binding to the phospholipid. Thus, these two regulatory steps are related.

The authors went on to determine how events combine at the structural level. Using computational modeling, NMR, and site-directed mutagenesis, they showed that dephosphorylation of Ser3 unblocked an amino-terminal actin-binding site on cofilin. Whereas at the other end of the protein, the decreased binding of PI(4,5)P2, after His133 deprotonation, freed up a second actin-binding site.

pH-dependent binding of membrane phospholipids is a growing phenomenon in protein biology, suggested to be a negative regulatory mechanism in some instances—as now shown for cofilin. It may be particularly relevant at the cell's leading edge where actin regulators can be kept close at hand, but remain inactive until needed.

Frantz, C., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200804161.[Abstract/Free Full Text]

Caitlin Sedwick

csedwick{at}gmail.com

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF, 1107K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sedwick, C. Search for Related Content PubMed Articles by Sedwick, C. Social Bookmarking                            What's this?