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

The p21-activated kinases (PAKs), stimulated by binding with GTP-liganded f orms of Cdc42 or Pac, modulate cytoskeletal actin assembly and activate MAP -kinase pathways. The 2.3 Angstrom resolution crystal structure of a comple x between the N-terminal autoregulatory fragment and the C-terminal kinase domain of PAK1 shows that GTPase binding will trigger a series of conformat ional changes, beginning with disruption of a PAK1 dimer and ending with re arrangement 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 b inding will refold part of the IS domain and unfold the rest. A related swi tch has been seen in the Wiskott-Aldrich syndrome protein (WASP).