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mDia1 as a possible coordinator of actin, focal adhesions and
microtubule assembly
Diaphanous related formin homology proteins (DRF) are ubiquitous, and are
found in mice, humans, Drosophila, C. elegans (Severson et al., 2002),
Aspergillus (Sharpless and Harris, 2002), and fission and budding yeast. A
mutation of this protein in Drosophila, called Diaphanous, affects cytokinesis
(Afshar et al., 2000; Castrillon and Wasserman, 1994). Structural organization
of DRF proteins is similar in different species and includes a small Rho-family
G-protein-binding domain at the N-terminus, several formin-homology
domains (FH1, FH2 and sometimes FH3) in the central part of the molecule,
and an auto-inhibitory domain (DAD) at the C-terminus (Alberts, 2001,
2002). In its 'closed' conformation, when DAD is bound to the N-terminus,
the molecule is inactive. Occupation of the DRF protein by Rho-GTP (or by
Cdc42-GTP in some DRF), in its binding site at the N-terminus, releases
DAD and converts the 'closed' conformation into an 'open' one, in which
formin homology domains are accessible to their ligands, rendering the entire
molecule biologically active (Figure 5.3). Truncated mutants of DRF
preserving the formin homology domains in the open conformation are
constitutively active (Tominaga et al., 2000; Watanabe et al., 1999).
One apparent function of DRF proteins is in the regulation of actin
assembly. In budding yeast, formins Bni1 and Bnr1 are necessary and
sucient for the assembly of elongated, tropomyosin-containing cables of
Figure 5.3 Activation of mDia by active RhoA. In its inactive state, mDia is thought to
exist in a closed conformation where its C-terminal auto-inhibitory domain (DAD) is
bound to the N-terminus. Upon binding of Rho-GTP to the Rho-binding domain (RBD)
at the N-terminus, the whole molecule unfolds and the binding sites for downstream
signalling molecules localized at the FH1 and FH2 domains become exposed. A
constitutively active form of mDia1 (mDia1 DN3), lacking the N-terminal domain,
contains intact FH1 and FH2 domains (see Watanabe et al., 1999)
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