Abstract
SummaryThe poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.
Highlights
Signal transduction often occurs through large and transient multi-protein complexes
We show that Tankyrase can induce Wnt-b-catenin signaling independently of its catalytic activity, through ARCand sterile alpha motif (SAM) domain-dependent scaffolding
Informed by crystal structures of the TNKS and TNKS2 SAM domains, we demonstrate that Tankyrase polymerization is critical for its function in Wnt signaling, required for full poly(ADP-ribose) polymerase (PARP) activity, and necessary for efficient interaction with AXIN
Summary
Signal transduction often occurs through large and transient multi-protein complexes. Polymerizing proteins can nucleate the assembly of higher-order structures termed signalosomes, which enable locally increased protein concentrations for efficient, transient, and spatially confined processes (Bienz, 2014; Wu, 2013). A destruction complex (DC) composed of the scaffolding proteins AXIN and adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK3), and casein kinase 1 (CK1) captures and phosphorylates b-catenin to initiate its degradation (Stamos and Weis, 2013). AXIN is the central and concentration-limiting component of the DC (Lee et al, 2003; Stamos and Weis, 2013). DCs manifest as dynamic puncta with a filamentous sub-organization, so-called b-catenin degradasomes, whose formation is dependent on AXIN polymerization (Fiedler et al, 2011; de la Roche et al, 2014; Martino-Echarri et al, 2016; Thorvaldsen et al, 2015)
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
