期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 21, 期 4, 页码 413-U163出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2781
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资金
- US National Institutes of Health (NIH) [R01 MH087950]
- NIH [T32 AR053461, GM095977]
- American Cancer Society [PF-13-033-01-DMC]
- Associazione Italiana per la Ricerca sul Cancro grant [IG-2013-14104]
- Industrial Macromolecular Crystallography Association through the Hauptman-Woodward Medical Research Institute
- US Department of Energy [DE-AC02-06CH11357]
The Rho family GTPase effector IRSp53 has essential roles in filopodia formation and neuronal development, but its regulatory mechanism is poorly understood. IRSp53 contains a membrane-binding BAR domain followed by an unconventional CRIB motif that overlaps with a proline-rich region (CRIB-PR) and an SH3 domain that recruits actin cytoskeleton effectors. Using a fluorescence reporter assay, we show that human IRSp53 adopts a closed inactive conformation that opens synergistically with the binding of human Cdc42 to the CRIB-PR and effector proteins, such as the tumor-promoting factor Eps8, to the SH3 domain. The crystal structure of Cdc42 bound to the CRIB-PR reveals a new mode of effector binding to Rho family GTPases. Structure-inspired mutations disrupt autoinhibition and Cdc42 binding in vitro and decouple Cdc42-and IRSp53-dependent filopodia formation in cells. The data support a combinatorial mechanism of IRSp53 activation.
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