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).
Lei
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Laboratory of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
Lu
W
W
Meng
W
W
Parrini
M C
MC
Eck
M J
MJ
Mayer
B J
BJ
Harrison
S C
SC
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
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