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Instruments / Technical Area	Publication Details	Published	Actions
Krios I-Titan Krios I at Diamond Krios II-Titan Krios II at Diamond Krios III-Titan Krios III at Diamond	Structural basis of tankyrase activation by polymerization Nisha Pillay , Laura Mariotti , Mariola Zaleska , Oviya Inian , Matthew Jessop , Sam Hibbs , Ambroise Desfosses , Paul C. R. Hopkins , Catherine M. Templeton , Fabienne Beuron , Edward P. Morris , Sebastian Guettler Nature 20 DOI: 10.1038/s41586-022-05449-8 Diamond Proposal Number(s): [28549, 15624, 16822, 16023, 21809] Open Access Show Abstract ▼ Abstract: The poly-ADP-ribosyltransferase tankyrase (TNKS, TNKS2) controls a wide range of disease-relevant cellular processes, including WNT–β-catenin signalling, telomere length maintenance, Hippo signalling, DNA damage repair and glucose homeostasis1,2. This has incentivized the development of tankyrase inhibitors. Notwithstanding, our knowledge of the mechanisms that control tankyrase activity has remained limited. Both catalytic and non-catalytic functions of tankyrase depend on its filamentous polymerization3,4,5. Here we report the cryo-electron microscopy reconstruction of a filament formed by a minimal active unit of tankyrase, comprising the polymerizing sterile alpha motif (SAM) domain and its adjacent catalytic domain. The SAM domain forms a novel antiparallel double helix, positioning the protruding catalytic domains for recurring head-to-head and tail-to-tail interactions. The head interactions are highly conserved among tankyrases and induce an allosteric switch in the active site within the catalytic domain to promote catalysis. Although the tail interactions have a limited effect on catalysis, they are essential to tankyrase function in WNT–β-catenin signalling. This work reveals a novel SAM domain polymerization mode, illustrates how supramolecular assembly controls catalytic and non-catalytic functions, provides important structural insights into the regulation of a non-DNA-dependent poly-ADP-ribosyltransferase and will guide future efforts to modulate tankyrase and decipher its contribution to disease mechanisms.	Nov 2022
I03-Macromolecular Crystallography	Tankyrase requires SAM domain-dependent polymerization to support Wnt-β-catenin signaling Laura Mariotti , Catherine m. Templeton , Michael Ranes , Patricia Paracuellos Torrecilla , Nora Cronin , Fabienne Beuron , Edward Morris , Sebastian Guettler Molecular Cell 63, 498 - 513 DOI: 10.1016/j.molcel.2016.06.019 Diamond Proposal Number(s): [8015, 10088] Show Abstract ▼ 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.	Aug 2016

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