Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.
The p21-activated kinases (PAKs), stimulated by binding with GTP-liganded forms of Cdc42 or Rac, modulate cytoskeletal actin assembly and activate MAP-kinase pathways. The 2.3 A resolution crystal structure of a complex between the N-terminal autoregulatory fragment and the C-terminal kinase domain of PAK1 shows that GTPase binding will trigger a ... series of conformational changes, beginning with disruption of a PAK1 dimer and ending with rearrangement of the kinase active site into a catalytically competent state. An inhibitory switch (IS) domain, which overlaps the GTPase binding region of PAK1, positions a polypeptide segment across the kinase cleft. GTPase binding will refold part of the IS domain and unfold the rest. A related switch has been seen in the Wiskott-Aldrich syndrome protein (WASP).
Mesh Terms:
Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Dimerization, Enzyme Activation, Enzyme Inhibitors, GTP Phosphohydrolases, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proteins, Recombinant Proteins, Sequence Homology, Amino Acid, Wiskott-Aldrich Syndrome Protein, p21-Activated Kinases
Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Dimerization, Enzyme Activation, Enzyme Inhibitors, GTP Phosphohydrolases, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proteins, Recombinant Proteins, Sequence Homology, Amino Acid, Wiskott-Aldrich Syndrome Protein, p21-Activated Kinases
Cell
Date: Aug. 04, 2000
PubMed ID: 10975528
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