1cee

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SOLUTION STRUCTURE OF CDC42 IN COMPLEX WITH THE GTPASE BINDING DOMAIN OF WASP

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act, as molecular switches in signalling pathways that regulate cytoskeletal, architecture, gene expression and progression of the cell cycle. Cdc42 and, Rac transmit many signals through GTP-dependent binding to effector, proteins containing a Cdc42/Rac-interactive-binding (CRIB) motif. One such, effector, the Wiskott-Aldrich syndrome protein (WASP), is postulated to, link activation of Cdc42 directly to the rearrangement of actin. Human, mutations in WASP cause severe defects in haematopoletic cell function, leading to clinical symptoms of thrombocytopenia, immunodeficiency and, eczema. Here we report the solution structure of a complex between, activated Cdc42 and a minimal GTPase-binding domain (GBD) from WASP. An, extended amino-terminal GBD peptide that includes the CRIB motif contacts, the switch I, beta2 and alpha5 regions of Cdc42. A carboxy-terminal, beta-hairpin and alpha-helix pack against switch II. The Phe-X-His-X2-His, portion of the CRIB motif and the alpha-helix appear to mediate, sensitivity to the nucleotide switch through contacts to residues 36-40 of, Cdc42. Discrimination between the Rho-family members is likely to be, governed by GBD contacts to the switch I and alpha5 regions of the, GTPases. Structural and biochemical data suggest that GBD-sequence, divergence outside the CRIB motif may reflect additional regulatory, interactions with functional domains that are specific to individual, effectors.

Disease

Known diseases associated with this structure: Neutropenia, severe congenital, X-linked OMIM:[300392], Thrombocytopenia, X-linked OMIM:[300392], Thrombocytopenia, X-linked, intermittent OMIM:[300392], Wiskott-Aldrich syndrome OMIM:[300392]

About this Structure

1CEE is a Protein complex structure of sequences from Homo sapiens with MG and GCP as ligands. Full crystallographic information is available from OCA.

Reference

Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein., Abdul-Manan N, Aghazadeh B, Liu GA, Majumdar A, Ouerfelli O, Siminovitch KA, Rosen MK, Nature. 1999 May 27;399(6734):379-83. PMID:10360578

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