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Structural and Biochemical Basis for the Inhibitory Effect of Liprin-?3 on Mouse Diaphanous 1 (mDia1) Function.

ABSTRACT: Diaphanous-related formins are eukaryotic actin nucleation factors regulated by an autoinhibitory interaction between the N-terminal RhoGTPase-binding domain (mDiaN) and the C-terminal Diaphanous-autoregulatory domain (DAD). Although the activation of formins by Rho proteins is well characterized, its inactivation is only marginally understood. Recently, liprin-?3 was shown to interact with mDia1. Overexpression of liprin-?3 resulted in a reduction of the cellular actin filament content. The molecular mechanisms of how liprin-?3 exerts this effect and counteracts mDia1 activation by RhoA are unknown. Here, we functionally and structurally define a minimal liprin-?3 core region, sufficient to recapitulate the liprin-?3 determined mDia1-respective cellular functions. We show that liprin-?3 alters the interaction kinetics and thermodynamics of mDiaN with RhoA·GTP and DAD. RhoA displaces liprin-?3 allosterically, whereas DAD competes with liprin-?3 for a highly overlapping binding site on mDiaN. Liprin-?3 regulates actin polymerization by lowering the regulatory potency of RhoA and DAD on mDiaN. We present a model of a mechanistically unexplored and new aspect of mDiaN regulation by liprin-?3.

PROVIDER: S-EPMC4505501 | BioStudies |

REPOSITORIES: biostudies

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Structure and activity of full-length formin mDia1.

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