Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Monday Speaker Abstracts

Control of Actin Filament Assembly by Multifunctional WASP- Homology 2 (WH2) Domains Marie-France Carlier , Julien Perrnier, Pierre Montaville, Balendu Avvaru, Antoine Jégou, Guillaume Romet-lemonne. CNRS, Gif-sur-Yvette, France. WH2 domains are widespread, intrinsically disordered, short (30 amino-acids) protein motifs that fold upon binding to actin. They are present, in single or repeated motifs, in about 100 proteins that play a role in cell motility and morphogenetic processes by regulating actin assembly. They all bind actin similarly, in particular inserting an amphipathic α-helix in a hydrophobic pocket at the shear zone between actin subdomains 1 and 3 at the barbed face of the actin monomer. Thus, they display a large variety of functions, from sequestration of monomeric actin or profilin-mimicking activity to regulation of filament barbed end dynamics and filament severing. We have analyzed the structural basis for the multifunctionality of several WH2 domain proteins like N-WASP, Spire, Cordon-bleu, VASP and the Vibrio cholerae effector VopF. We show that 1) discrete sequence variations underlie differences in function ; 2) binding of WH2 to barbed end terminal subunits allows barbed end capping by Spire, an essential feature of its synergy with formin 2 in meiosis ; 3) a combination of profilin-like activity, filament severing and ADP-G-actin sequestering generates enhanced filament dynamics and oscillatory polymerization of actin ; 4) dimerization of WH2 domains allows filament barbed end tracking and potential processive assembly in VASP and VopF. References : • Hertzog et al., 2004, Cell 117, 611-623. • Bosch et al., 2007, Mol. Cell 28, 555-568. • Husson et al., 2011, Cordon-Bleu uses WH2 domains as multifunctional dynamizers of actin filament assembly. Mol. Cell 43, 464-477. • Carlier 2011 Nat. Struct. Mol. Biol. 18, 967-969. • Pernier et al., 2013, Nat. Struct. Mol. Biol. 20, 1069-1076. • Montaville et al., 2014, PloS Biol. 12, e1001795.

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