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A more recent version of this article appeared on February 1, 2004
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Submitted on August 24, 2003
Revised on October 9, 2003
Accepted on October 12, 2003
1 Department of Biology and The Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454, USA, The first two authors contributed equally to this work
2 Departments of Pediatric Oncology, The Dana-Farber Cancer Institute and Pediatric Hematology, The Children’s Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA, The first two authors contributed equally to this work
3 Department of Biology and The Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454, USA
4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115
5 Departments of Pediatric Oncology, The Dana-Farber Cancer Institute and Pediatric Hematology, The Children’s Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
* Corresponding author. E-mail address: goode{at}brandeis.edu.
Formins have conserved roles in cell polarity and cytokinesis and directly nucleate actin filament assembly through their FH2 domain. Here, we define the active region of the yeast formin Bni1 FH2 domain and show that it dimerizes. Mutations that disrupt dimerization abolish actin assembly activity, suggesting that dimers are the active state of the FH2 domains. The Bni1 FH2 domain protects growing barbed ends of actin filaments from vast excesses of capping protein, suggesting that the dimer maintains a persistent association during elongation. This is not a species-specific mechanism, as the activities of purified mammalian formin mDia1 are identical to those of Bni1. Further, mDia1 partially complements BNI1 function in vivo, and expression of a dominant active mDia1 construct in yeast causes similar phenotypes to dominant active Bni1 constructs. In addition, we purified the Bni1-interacting half of the cell polarity factor Bud6 and found that it binds specifically to actin monomers and, like profilin, promotes rapid nucleotide exchange on actin. Bud6 and profilin show additive stimulatory effects on Bni1 activity and have a synthetic lethal genetic interaction in vivo. From these results, we propose a model in which Bni1 FH2 dimers nucleate and processively cap the elongating barbed end of the actin filament, while Bud6 and profilin generate a local flux of ATP-actin monomers to promote actin assembly.
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