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Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.

Cell | Aug 4, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10975528

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 RIS Download

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