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J. Biol. Chem., Vol. 282, Issue 41, 30120-30130, October 12, 2007

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The Diaphanous Inhibitory Domain/Diaphanous Autoregulatory Domain Interaction Is Able to Mediate Heterodimerization between mDia1 and mDia2^*

Sarah J. Copeland, Brenda J. Green, Sarah Burchat, Giuseppe A. Papalia, David Banner, and John W. Copeland¹

From the Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and Centre for Biomolecular Interaction Analysis, School of Medicine, University of Utah, Salt Lake City, Utah 84312

Formins are multidomain proteins that regulate numerous cytoskeleton-dependent cellular processes. These effects are mediated by the presence of two regions of homology, formin homology 1 and FH2. The diaphanous-related formins (DRFs) are distinguished by the presence of interacting N- and C-terminal regulatory domains. The GTPase binding domain and diaphanous inhibitory domain (DID) are found in the N terminus and bind to the diaphanous autoregulatory domain (DAD) found in the C terminus. Adjacent to the DID is an N-terminal dimerization motif (DD) and coiled-coil region (CC). The N terminus of Dia1 is also proposed to contain a Rho-independent membrane-targeting motif. We undertook an extensive structure/function analysis of the mDia1 N terminus to further our understanding of its role in vivo. We show here that both DID and DD are required for efficient autoinhibition in the context of full-length mDia1 and that the DD of mDia1 and mDia2, like formin homology 2, mediates homo- but not heterodimerization with other DRF family members. In contrast, our results suggest that the DID/DAD interaction mediates heterodimerization of full-length mDia1 and mDia2 and that the auto-inhibited conformation of DRFs is oligomeric. In addition, we also show that the DD/CC region is required for the Rho-independent membrane targeting of the isolated N terminus.

Received for publication, May 9, 2007 , and in revised form, August 21, 2007.

^* This work was supported by Canadian Institutes of Health Research Operating Grant 68816 (to J. W. C.). 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.

¹ To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, ON, Canada, K1H 8M5. Tel.: 613-562-5800; Fax: 613-562-5636; E-mail: john.copeland{at}uottawa.ca.

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