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dc.contributor.authorMariotti, L
dc.contributor.authorTempleton, CM
dc.contributor.authorRanes, M
dc.contributor.authorParacuellos, P
dc.contributor.authorCronin, N
dc.contributor.authorBeuron, F
dc.contributor.authorMorris, E
dc.contributor.authorGuettler, S
dc.date.accessioned2016-08-18T10:05:52Z
dc.date.issued2016-08-04
dc.identifier.citationMolecular cell, 2016, 63 (3), pp. 498 - 513
dc.identifier.issn1097-2765
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/66
dc.identifier.eissn1097-4164
dc.identifier.doi10.1016/j.molcel.2016.06.019
dc.description.abstractThe 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.
dc.formatPrint
dc.format.extent498 - 513
dc.languageeng
dc.language.isoeng
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHela Cells
dc.subjectHumans
dc.subjectPoly(ADP-ribose) Polymerases
dc.subjectTankyrases
dc.subjectDrosophila Proteins
dc.subjectCrystallography
dc.subjectTransfection
dc.subjectBinding Sites
dc.subjectProtein Conformation
dc.subjectProtein Binding
dc.subjectStructure-Activity Relationship
dc.subjectMutation
dc.subjectCatalysis
dc.subjectModels, Molecular
dc.subjectProtein Multimerization
dc.subjectHEK293 Cells
dc.subjectAxin Protein
dc.subjectWnt Signaling Pathway
dc.subjectCaspase Activation and Recruitment Domain
dc.subjectSterile Alpha Motif
dc.titleTankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
dc.typeJournal Article
dcterms.dateAccepted2016-06-13
rioxxterms.versionofrecord10.1016/j.molcel.2016.06.019
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cell
pubs.issue3
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Electron Microscopy
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Electron Microscopy
pubs.publication-statusPublished
pubs.volume63
pubs.embargo.termsNo embargo
icr.researchteamStructural Biology of Cell Signalling
icr.researchteamStructural Electron Microscopy
dc.contributor.icrauthorRanes, Michael
dc.contributor.icrauthorBeuron, Fabienne
dc.contributor.icrauthorMorris, Edward
dc.contributor.icrauthorGuettler, Sebastian


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