Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.
The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex. Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery. These data show that 'intrinsically unstructured' peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context.
Kim
A S
AS
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kakalis
L T
LT
Abdul-Manan
N
N
Liu
G A
GA
Rosen
M K
MK
D000595:Amino Acid Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D003001:Cloning, Molecular; D005656:Fungal Proteins / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008840:Microfilament Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013816:Thermodynamics; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D005656:Fungal Proteins; D008840:Microfilament Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; C090350:VRP1 protein, S cerevisiae; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein