4JS0

Complex of Cdc42 with the CRIB-PR domain of IRSp53

Summary for 4JS0

• Entry DOI: 10.2210/pdb4js0/pdb
• Descriptor: Cell division control protein 42 homolog, Brain-specific angiogenesis inhibitor 1-associated protein 2, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (6 entities in total)
• Functional Keywords: gtpase binding domain, crib domain, cytoskeleton regulation, signaling protein-signaling protein complex, signaling protein/signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side (Potential): P60953; Cytoplasm: Q9UQB8
• Total number of polymer chains: 2
• Total formula weight: 24739.77

Authors

Kast, D.J.,Dominguez, R. (deposition date: 2013-03-22, release date: 2014-03-05, Last modification date: 2024-02-28)

Primary citation

Kast, D.J.,Yang, C.,Disanza, A.,Boczkowska, M.,Madasu, Y.,Scita, G.,Svitkina, T.,Dominguez, R.
Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors.
Nat.Struct.Mol.Biol., 21:413-422, 2014

PubMed 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.

PubMed: 24584464
DOI: 10.1038/nsmb.2781

Experimental method

X-RAY DIFFRACTION (1.9 Å)