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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).

Pubmed ID: 10975528


  • Lei M
  • Lu W
  • Meng W
  • Parrini MC
  • Eck MJ
  • Mayer BJ
  • Harrison SC



Publication Data

August 4, 2000

Associated Grants

  • Agency: NCI NIH HHS, Id: 1R01 CA2258-01

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