Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch

Cell. 2000 Aug 4;102(3):387-97. doi: 10.1016/s0092-8674(00)00043-x.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Dimerization
  • Enzyme Activation
  • Enzyme Inhibitors
  • GTP Phosphohydrolases / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Proteins / chemistry
  • Recombinant Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Wiskott-Aldrich Syndrome Protein
  • p21-Activated Kinases

Substances

  • Enzyme Inhibitors
  • Peptide Fragments
  • Proteins
  • Recombinant Proteins
  • Wiskott-Aldrich Syndrome Protein
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • GTP Phosphohydrolases

Associated data

  • PDB/1F3M