Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
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Embargo End Date
Authors
Mariotti, L
Templeton, CM
Ranes, M
Paracuellos, P
Cronin, N
Beuron, F
Morris, E
Guettler, S
Templeton, CM
Ranes, M
Paracuellos, P
Cronin, N
Beuron, F
Morris, E
Guettler, S
Document Type
Journal Article
Date
2016-08-04
Date Accepted
2016-06-13
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.
Citation
Molecular cell, 2016, 63 (3), pp. 498 - 513
Source Title
Publisher
CELL PRESS
ISSN
1097-2765
eISSN
1097-4164
Collections
Research Team
Structural Biology of Cell Signalling
Structural Electron Microscopy
Structural Electron Microscopy