title: Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate.
abstract: The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not β-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Ha
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Catherine
authors.initials: C
authors.lastname: Chen
authors.forename: Hua Jane
authors.initials: HJ
authors.lastname: Lou
authors.forename: Jia
authors.initials: J
authors.lastname: Gao
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D020134:Catalytic Domain / Q000235:genetics; D018360:Crystallography, X-Ray; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D051025:bcl-Associated Death Protein; C103302:STAC protein, human; C116367:PAK4 protein, human; D054462:p21-Activated Kinases