title: Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.
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).
authors.affiliation: Laboratory of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lei
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: W
authors.initials: W
authors.lastname: Meng
authors.forename: M C
authors.initials: MC
authors.lastname: Parrini
authors.forename: M J
authors.initials: MJ
authors.lastname: Eck
authors.forename: B J
authors.initials: BJ
authors.lastname: Mayer
authors.forename: S C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D020558:GTP Phosphohydrolases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D051316:Wiskott-Aldrich Syndrome Protein; D054462:p21-Activated Kinases
chemical_list: D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins; D051316:Wiskott-Aldrich Syndrome Protein; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020558:GTP Phosphohydrolases