Chereau, D. et al. Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. Proc. Natl Acad. Sci. USA 102, 16644-16649

Boston Biomedical Research Institute, Watertown, MA 02472, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2005; 102(46):16644-9. DOI: 10.1073/pnas.0507021102
Source: PubMed

ABSTRACT Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2/3 complex. Here we describe the crystal structures of complexes of actin with the WH2 domains of WASP, WASP-family verprolin homologous protein, and WASP-interacting protein. Despite low sequence identity, WH2 shares structural similarity with the N-terminal portion of the actin monomer-sequestering thymosin beta domain (Tbeta). We show that both domains inhibit nucleotide exchange by targeting the cleft between actin subdomains 1 and 3, a common binding site for many unrelated actin-binding proteins. Importantly, WH2 is significantly shorter than Tbeta but binds actin with approximately 10-fold higher affinity. WH2 lacks a C-terminal extension that in Tbeta4 becomes involved in monomer sequestration by interfering with intersubunit contacts in F-actin. Owing to their shorter length, WH2 domains connected in tandem by short linkers can coexist with intersubunit contacts in F-actin and are proposed to function in filament nucleation by lining up actin subunits along a filament strand. The WH2-central region of WASP-family proteins is proposed to function in an analogous way by forming a special class of tandem repeats whose function is to line up actin and Arp2 during Arp2/3 nucleation. The structures also suggest a mechanism for how profilin-binding Pro-rich sequences positioned N-terminal to WH2 could feed actin monomers directly to WH2, thereby playing a role in filament elongation.

  • Source
    • "The interactions of the LKKT(V) domain are for the most part electrostatic in character, with positively charged residues of the WH2 domain facing negatively charged residues on the actin surface (Chereau et al., 2005; Dominguez, 2007; Lee and Dominguez, 2010). Exportin-6 has the similar motif (LKPS) near residue 765, which corresponds to helix14A. "
    [Show description] [Hide description]
    DESCRIPTION: Review on nuclear transport with focus mainly on Exportin 6. Predicted structure and predicted mechanism of interaction.
  • Source
    • "In cells actin treadmilling is enhanced by the combined nucleotide-dependent activities of ABPs (Didry et al., 1998; Renault et al., 2008). The formin family of proteins and the actin-related protein (Arp)2/3 complex machinery can catalyze the de novo assembly of actin filaments preferentially by binding to the ATP-bound actin units (Chereau et al., 2005; Ichetovkin et al., 2002; Romero et al., 2007). The disassembly of actin filaments can be enhanced by members of the ADF-H domain-containing ADF/cofilin proteins, which preferentially bind to the ADP-loaded regions of the filaments and accelerate the dissociation of actin subunits (Blanchoin and Pollard, 1999; Carlier et al., 1997; Suarez et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several cellular processes rely on the fine tuning of actin cytoskeleton. A central component in the regulation of this cellular machinery is the ADF-H domain proteins. Despite sharing the same domain, ADF-H domain proteins produce a diverse functional landscape in the regulation of the actin cytoskeleton. Recent findings emphasize that the functional and structural features of these proteins can differ not only between ADF-H families but even within the same family. The structural and evolutional background of this functional diversity is poorly understood. This review focuses on the specific functional characteristics of ADF-H domain proteins and how these features can be linked to structural differences in the ADF-H domain and also to different conformational transitions in actin. In the light of recent discoveries we pay special attention to the ADF/cofilin proteins to find tendencies along which the functional and structural diversification is governed through the evolution.
    European Journal of Cell Biology 05/2014; 93(5-6). DOI:10.1016/j.ejcb.2013.12.001 · 3.70 Impact Factor
    • "Presumably, the effects of the xAB would be manifested at the tip of stereocilia, where we found large espin isoforms to be concentrated. Although barbed-end capping by espins alone seems unlikely (Loomis et al., 2006), espins contain a WH2 domain, which raises the possibility of interactions with actin monomer (Paunola et al., 2002; Chereau et al., 2005) and the filament barbed end (Co et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The espin actin-bundling proteins, which are produced in different sized isoforms from a single gene, are required for the growth of hair cell stereocilia. We have characterized an additional actin filament-binding site present in the extended amino termini of large espin isoforms. Constitutively active in espin 2, the site increased the size of actin bundles formed in vitro and inhibited actin fluorescence recovery in microvilli. In espin 1, which has an amino-terminal ankyrin repeat domain, the site was autoinhibited by binding between the ankyrin repeat domain and a peptide near the actin-binding site. Deletion of this peptide from espin 1 activated its actin-binding site. The peptide resembled tail homology domain I of myosin III, a ligand of the ankyrin repeat domain localized with espin 1 at the tip of stereocilia. A myosin III tail homology domain I peptide, but not scrambled control peptides, inhibited internal binding of the ankyrin repeat domain and released the espin 1 actin-binding site from autoinhibition. This regulation could result in local activation of the additional actin-binding site of espin 1 by myosin III in stereocilia.
    Journal of Cell Science 01/2014; 127(6). DOI:10.1242/jcs.143255 · 5.33 Impact Factor
Show more


Available from