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J. Biol. Chem., Vol. 281, Issue 20, 14383-14392, May 19, 2006

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Mechanistic Differences in Actin Bundling Activity of Two Mammalian Formins, FRL1 and mDia2^*

Elizabeth S. Harris¹, Isabelle Rouiller, Dorit Hanein, and Henry N. Higgs, Supported by National Institutes of Health Grant GM-069818 and a Pew Biomedical Scholars award²

From the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755 and the Cell Adhesion Program, The Burnham Institute, La Jolla, California 92037

Formin proteins are regulators of actin dynamics, mediating assembly of unbranched actin filaments. These multidomain proteins are defined by the presence of a Formin Homology 2 (FH2) domain. Previous work has shown that FH2 domains bind to filament barbed ends and move processively at the barbed end as the filament elongates. Here we report that two FH2 domains, from mammalian FRL1 and mDia2, also bundle filaments, whereas the FH2 domain from mDia1 cannot under similar conditions. The FH2 domain alone is sufficient for bundling. Bundled filaments made by either FRL1 or mDia2 are in both parallel and anti-parallel orientations. A novel property that might contribute to bundling is the ability of the dimeric FH2 domains from both FRL1 and mDia2 to dissociate and recombine. This property is not observed for mDia1. A difference between FRL1 and mDia2 is that FRL1-mediated bundling is competitive with barbed end binding, whereas mDia2-mediated bundling is not. Mutation of a highly conserved isoleucine residue in the FH2 domain does not inhibit bundling by either FRL1 or mDia2, but inhibits barbed end activities. However, the severity of this mutation varies between formins. For mDia1 and mDia2, the mutation strongly inhibits all effects of barbed end binding, but affects FRL1 much less strongly. Furthermore, our results suggest that the Ile mutation affects processivity. Taken together, our data suggest that the bundling activities of FRL1 and mDia2, while producing phenotypically similar bundles, differ in mechanistic detail.

Received for publication, October 6, 2005 , and in revised form, March 20, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ Supported by National Institutes of Health Training Grant T32 GM08704.

² To whom correspondence should be addressed. Tel.: 603-650-1420; Fax: 603-650-1128. E-mail: henry.higgs{at}dartmouth.edu.

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