Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling

Summary The 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.
Graphical Abstract
Highlights • SAM domain crystal structures reveal mechanism of Tankyrase polymerization • Catalysis-independent Tankyrase scaffolding drives Wnt-β-catenin signaling • Tankyrase polymerization supports PARP activity and AXIN binding
Catalysis-independent scaffolding by Tankyrase supports Wnt-β-catenin signaling. Scaffolding is mediated by AXIN-binding ankyrin repeat clusters and a polymerizing SAM domain. In a structure-function approach, Mariotti et al. show that polymerization supports Tankyrase PARP activity and enables avidity-dependent AXIN binding.