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Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors.

Authors :
Kast, David J
Yang, Changsong
Disanza, Andrea
Boczkowska, Malgorzata
Madasu, Yadaiah
Scita, Giorgio
Svitkina, Tatyana
Dominguez, Roberto
Source :
Nature Structural & Molecular Biology. Apr2014, Vol. 21 Issue 4, p413-422. 10p.
Publication Year :
2014

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15459993
Volume :
21
Issue :
4
Database :
Academic Search Index
Journal :
Nature Structural & Molecular Biology
Publication Type :
Academic Journal
Accession number :
95393701
Full Text :
https://doi.org/10.1038/nsmb.2781