Structural and biochemical basis for the inhibitory effect of liprin-{alpha}3 on mouse Diaphanous 1 (mDia1) function [Protein Structure and Folding]

April 24th, 2015 by Brenig, J., de Boor, S., Knyphausen, P., Kuhlmann, N., Wroblowski, S., Baldus, L., Scislowski, L., Artz, O., Trauschies, P., Baumann, U., Neundorf, I., Lammers, M.

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). While the activation of formins by Rho-proteins is well characterized, its inactivation is only marginally understood. Recently, liprin-α3 was shown to interact with mDia1. Overexpression of liprin-α3 resulted in a reduction of the cellular actin-filament content. The molecular mechanisms how liprin-α3 exerts this effect and counteracts mDia1 activation by RhoA are unknown. Here, we functionally and structurally define a minimal liprin-α3-core region (LCR), sufficient to recapitulate the liprin-α3 determined mDia1-respective cellular functions. We show that liprin-α3 alters the interaction-kinetics and -thermodynamics of mDiaN with RhoA-GTP and DAD. RhoA displaces liprin-α3 allosterically, whereas DAD competes with liprin-α3 for a highly overlapping binding site on mDiaN. liprin-α3 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 in mDiaN regulation by liprin-α3.
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