Homo-oligomerization is essential for F-actin assembly by the formin family FH2 domain

John W Copeland, Sarah J Copeland, Richard Treisman
Journal of Biological Chemistry 2004 November 26, 279 (48): 50250-6
Formin proteins regulate the actin and microtubule cytoskeletons and also control the activity of the SRF transcription factor through depletion of the G-actin pool. Although the conserved formin homology 2 (FH2) domains of the mDia1 and Bni1 formins can nucleate actin polymerization in vitro, the activity of other FH2 domains and the relationship between actin polymerization and microtubule reorganization have been controversial. We show that, similar to the mDia1 FH2 domain, the FH2 domains of mDia2 and ld are sufficient for SRF activation in vivo. We demonstrate that an mDia1 mutant defective for microtubule rearrangement in vivo is also defective in SRF activation in vivo as well as actin polymerization in vitro and that the mDia2 FH2 domain promotes actin polymerization in vitro. Using co-immunoprecipitation, we show that mDia1 is oligomeric in its inactive autoinhibited state in vivo, that the active mDia1 and mDia2 FH2 domains form homo- but not hetero-oligomers in vivo, and that oligomerization is abolished by inactivating FH2 deletion and point mutations. Nevertheless, inactive mDia1 FH2 domain mutants retain the ability to interfere with cellular mDia activity. Our results show that self-oligomerization is essential for SRF activation in vivo and F-actin assembly in vitro and provide strong support for recent structural models of the FH2 domain.

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