title: Structural insights into the autoactivation mechanism of p21-activated protein kinase.
abstract: p21-activated kinases (PAKs) play an important role in diverse cellular processes. Full activation of PAKs requires autophosphorylation of a critical threonine/serine located in the activation loop of the kinase domain. Here we report crystal structures of the phosphorylated and unphosphorylated PAK1 kinase domain. The phosphorylated PAK1 kinase domain has a conformation typical of all active protein kinases. Interestingly, the structure of the unphosphorylated PAK1 kinase domain reveals an unusual dimeric arrangement expected in an authentic enzyme-substrate complex, in which the activation loop of the putative "substrate" is projected into the active site of the "enzyme." The enzyme is bound to AMP-PNP and has an active conformation, whereas the substrate is empty and adopts an inactive conformation. Thus, the structure of the asymmetric homodimer mimics a trans-autophosphorylation complex, and suggests that unphosphorylated PAK1 could dynamically adopt both the active and inactive conformations in solution.
authors.affiliation: MOE Key Laboratory for Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: C515903:PAK1 protein, human; D054462:p21-Activated Kinases