PMID- 10360578
OWN - NLM
STAT- MEDLINE
DCOM- 19990616
LR  - 20061115
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 399
IP  - 6734
DP  - 1999 May 27
TI  - Structure of Cdc42 in complex with the GTPase-binding domain of the
      'Wiskott-Aldrich syndrome' protein.
PG  - 379-83
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, 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.
FAU - Abdul-Manan, N
AU  - Abdul-Manan N
AD  - Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer
      Center, New York, New York 10021, USA.
FAU - Aghazadeh, B
AU  - Aghazadeh B
FAU - Liu, G A
AU  - Liu GA
FAU - Majumdar, A
AU  - Majumdar A
FAU - Ouerfelli, O
AU  - Ouerfelli O
FAU - Siminovitch, K A
AU  - Siminovitch KA
FAU - Rosen, M K
AU  - Rosen MK
LA  - eng
SI  - PDB/1CEE
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (WAS protein, human)
RN  - 0 (Wiskott-Aldrich Syndrome Protein)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 3.6.5.2 (cdc42 GTP-Binding Protein)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Cell Cycle Proteins/*chemistry/metabolism
MH  - Crystallography, X-Ray
MH  - Escherichia coli
MH  - GTP Phosphohydrolases/chemistry/metabolism
MH  - GTP-Binding Proteins/*chemistry/metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Protein Binding
MH  - Proteins/*chemistry/metabolism
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Sequence Homology, Amino Acid
MH  - *Wiskott-Aldrich Syndrome
MH  - Wiskott-Aldrich Syndrome Protein
MH  - cdc42 GTP-Binding Protein
EDAT- 1999/06/09 10:00
MHDA- 2001/03/23 10:01
CRDT- 1999/06/09 10:00
PHST- 1999/06/09 10:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/06/09 10:00 [entrez]
AID - 10.1038/20726 [doi]
PST - ppublish
SO  - Nature. 1999 May 27;399(6734):379-83. doi: 10.1038/20726.