The active conformation of the PAK1 kinase domain.
The p21-activated kinases (PAKs) participate in cytoskeletal control networks, downstream of Rho-family GTPases. A structure of PAK1 in an autoregulated, "off" state showed that a regulatory region, N-terminal to the kinase domain, forces the latter into an inactive conformation, prevents phosphorylation of Thr423 in the activation loop, and promotes dimerization. We have now determined structures at 1.8 A resolution for the free PAK1 kinase domain, with a mutation in the active site that blocks enzymatic activity, and for the same domain with a "phosphomimetic" mutation in the activation loop. The two very similar structures show that even in the absence of a phosphorylated Thr423, the kinase has an essentially active conformation. When Cdc42 binds the regulatory region and dissociates the dimer, PAK1 will be in an "intermediate-active" state, with a capacity to phosphorylate itself or other substrates even prior to modification of its activation loop.
Lei
Ming
M
Laboratory of Molecular Medicine, Children's Hospital, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
Robinson
Michael A
MA
Harrison
Stephen C
SC
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014961:X-Ray Diffraction; D054462:p21-Activated Kinases
D000255:Adenosine Triphosphate; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases