title: Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
abstract: 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.
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Laura
authors: L
authors: Mariotti
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Catherine M
authors: CM
authors: Templeton
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Michael
authors: M
authors: Ranes
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Patricia
authors: P
authors: Paracuellos
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Nora
authors: N
authors: Cronin
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Fabienne
authors: F
authors: Beuron
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
authors: Edward
authors: E
authors: Morris
authors: Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK. Electronic address: sebastian.guettler@icr.ac.uk.
authors: Sebastian
authors: S
authors: Guettler
mesh_terms: D060466:Axin Protein / Q000378:metabolism; D001665:Binding Sites; D000071476:Caspase Activation and Recruitment Domain; D002384:Catalysis; D003461:Crystallography; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D000071682:Sterile Alpha Motif; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D060449:Wnt Signaling Pathway
chemical_list: D060466:Axin Protein; D029721:Drosophila Proteins; D011065:Poly(ADP-ribose) Polymerases; D038501:Tankyrases; C555451:AXIN1 protein, human; C437334:TNKS2 protein, human; C418109:TNKS protein, human