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Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53
Author(s) -
Millard Thomas H,
Bompard Guillaume,
Heung Man Yeung,
Dafforn Timothy R,
Scott David J,
Machesky Laura M,
Fütterer Klaus
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600535
Subject(s) - biology , filopodia , homology (biology) , microbiology and biotechnology , sequence homology , computational biology , genetics , peptide sequence , actin , gene
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.