Abstract
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).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Crystallography, X-Ray
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Dimerization
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Enzyme Activation
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Enzyme Inhibitors
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GTP Phosphohydrolases / metabolism
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Models, Molecular
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / genetics
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Protein Structure, Tertiary
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Proteins / chemistry
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Recombinant Proteins / chemistry
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Sequence Homology, Amino Acid
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Wiskott-Aldrich Syndrome Protein
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p21-Activated Kinases
Substances
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Enzyme Inhibitors
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Peptide Fragments
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Proteins
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Recombinant Proteins
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Wiskott-Aldrich Syndrome Protein
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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GTP Phosphohydrolases