title: Striatins contain a noncanonical coiled coil that binds protein phosphatase 2A A subunit to form a 2:2 heterotetrameric core of striatin-interacting phosphatase and kinase (STRIPAK) complex.
abstract: The protein phosphatase 2A (PP2A) and kinases such as germinal center kinase III (GCKIII) can interact with striatins to form a supramolecular complex called striatin-interacting phosphatase and kinase (STRIPAK) complex. Despite the fact that the STRIPAK complex regulates multiple cellular events, it remains only partially understood how this complex itself is assembled and regulated for differential biological functions. Our recent work revealed the activation mechanism of GCKIIIs by MO25, as well as how GCKIIIs heterodimerize with CCM3, a molecular bridge between GCKIII and striatins. Here we dissect the structural features of the coiled coil domain of striatin 3, a novel type of PP2A regulatory subunit that functions as a scaffold for the assembly of the STRIPAK complex. We have determined the crystal structure of a selenomethionine-labeled striatin 3 coiled coil domain, which shows it to assume a parallel dimeric but asymmetric conformation containing a large bend. This result combined with a number of biophysical analyses provide evidence that the coiled coil domain of striatin 3 and the PP2A A subunit form a stable core complex with a 2:2 stoichiometry. Structure-based mutational studies reveal that homodimerization of striatin 3 is essential for its interaction with PP2A and therefore assembly of the STRIPAK complex. Wild-type striatin 3 but not the mutants defective in PP2A binding strongly suppresses apoptosis of Jurkat cells induced by the GCKIII kinase MST3, most likely through a mechanism in which striatin recruits PP2A to negatively regulate the activation of MST3. Collectively, our work provides structural insights into the organization of the STRIPAK complex and will facilitate further functional studies.
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Chen
authors.forename: Zhubing
authors.initials: Z
authors.lastname: Shi
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yicui
authors.initials: Y
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: Feng
authors.forename: Wenjia
authors.initials: W
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jerry H
authors.initials: JH
authors.lastname: Brown
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D000081410:Germinal Center Kinases; D006801:Humans; D019169:Jurkat Cells; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D000099317:Hippo Kinases
chemical_list: D001324:Autoantigens; D002148:Calmodulin-Binding Proteins; D000081410:Germinal Center Kinases; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; C405682:STRN3 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases; C517189:PPP2CA protein, human
keywords: Apoptosis; Coiled Coil; PP2A; Parallel Dimer; Phosphatase; Protein Complexes; Protein Kinases; Protein Structure; STRIPAK Complex; Striatin