TY - JOUR
T1 - Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein
AU - Abdul-Manan, Norzehan
AU - Aghazadeh, Behzad
AU - Liu, Grace A.
AU - Majumdar, Ananya
AU - Ouerfelli, Ouathek
AU - Simlnovitch, Katherine A.
AU - Rosen, Michael K.
PY - 1999/5/27
Y1 - 1999/5/27
N2 - 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, β2 and α5 regions of Cdc42. A carboxy-terminal β-hairpin and α-helix pack against switch II. The Phe- X-His-X2-His portion of the CRIB motif and the α-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 α5 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.
AB - 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, β2 and α5 regions of Cdc42. A carboxy-terminal β-hairpin and α-helix pack against switch II. The Phe- X-His-X2-His portion of the CRIB motif and the α-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 α5 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.
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U2 - 10.1038/20726
DO - 10.1038/20726
M3 - Article
C2 - 10360578
AN - SCOPUS:0033609388
SN - 0028-0836
VL - 399
SP - 379
EP - 383
JO - Nature
JF - Nature
IS - 6734
ER -