Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
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Date
2016-08-04Author
Mariotti, L
Templeton, CM
Ranes, M
Paracuellos, P
Cronin, N
Beuron, F
Morris, E
Guettler, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Hela Cells
Humans
Poly(ADP-ribose) Polymerases
Tankyrases
Drosophila Proteins
Crystallography
Transfection
Binding Sites
Protein Conformation
Protein Binding
Structure-Activity Relationship
Mutation
Catalysis
Models, Molecular
Protein Multimerization
HEK293 Cells
Axin Protein
Wnt Signaling Pathway
Caspase Activation and Recruitment Domain
Sterile Alpha Motif
Research team
Structural Biology of Cell Signalling
Structural Electron Microscopy
Language
eng
Date accepted
2016-06-13
License start date
2016-08
Citation
Molecular cell, 2016, 63 (3), pp. 498 - 513
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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