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.
Highlights
Striatins are novel regulatory subunits of phosphatase 2A (PP2A) in the striatin-interacting phosphatase and kinase (STRIPAK) complex
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
Striatin-interacting phosphatase and kinase (STRIPAK)4 is a recently identified supramolecular complex, in which striatins act as molecular scaffolds to recruit the protein phosphatase 2A (PP2A) and kinases including germinal center kinases (GCKs) (Fig. 1A) [1,2,3]
Summary
Striatins are novel regulatory subunits of PP2A in the striatin-interacting phosphatase and kinase (STRIPAK) complex. 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. Striatin-interacting phosphatase and kinase (STRIPAK) is a recently identified supramolecular complex, in which striatins act as molecular scaffolds to recruit the protein phosphatase 2A (PP2A) and kinases including germinal center kinases (GCKs) (Fig. 1A) [1,2,3]. The functional importance of striatin dimerization is further supported by our finding that overexpression of wild-type striatin 3, but not dimerization defective mutants, inhibited MST3-induced apoptosis in Jurkat cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
