Article
- The EMBO Journal (2005) 24, 240 - 250
- doi:10.1038/sj.emboj.7600535
Published online: 6 January 2005
Subject Categories:
Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53
Thomas H Millard1, Guillaume Bompard1, Man Yeung Heung1, Timothy R Dafforn1, David J Scott2, Laura M Machesky1 and Klaus Fütterer1
- School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, UK
- National Centre for Macromolecular Hydrodynamics, School of Biosciences, University of Nottingham, Sutton Bonington, UK
Correspondence to:
Klaus Fütterer, School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel: +44 121 414 5895; Fax: +44 121 414 5925; E-mail: k.futterer@bham.ac.uk
Received 27 October 2004; Accepted 6 December 2004
Abstract
The scaffolding protein insulin receptor tyrosine kinase substrate p53 (IRSp53), a ubiquitous regulator of the actin cytoskeleton, mediates filopodia formation under the control of Rho-family GTPases. IRSp53 comprises a central SH3 domain, which binds to proline-rich regions of a wide range of actin regulators, and a conserved N-terminal IRSp53/MIM homology domain (IMD) that harbours F-actin-bundling activity. Here, we present the crystal structure of this novel actin-bundling domain revealing a coiled-coil domain that self-associates into a 180 Å-long zeppelin-shaped dimer. Sedimentation velocity experiments confirm the presence of a single molecular species of twice the molecular weight of the monomer in solution. Mutagenesis of conserved basic residues at the extreme ends of the dimer abrogated actin bundling in vitro and filopodia formation in vivo, demonstrating that IMD-mediated actin bundling is required for IRSp53-induced filopodia formation. This study promotes an expanded view of IRSp53 as an actin regulator that integrates scaffolding and effector functions.
Keywords:
- actin bundling,
- cell motility,
- filopodia,
- IRSp53,
- X-ray crystallography
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