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Structural basis of tankyrase activation by polymerization

DOI: 10.1038/s41586-022-05449-8 DOI Help

Authors: Nisha Pillay (The Institute of Cancer Research (ICR)) , Laura Mariotti (The Institute of Cancer Research (ICR)) , Mariola Zaleska (The Institute of Cancer Research (ICR)) , Oviya Inian (The Institute of Cancer Research (ICR)) , Matthew Jessop (The Institute of Cancer Research (ICR)) , Sam Hibbs (The Institute of Cancer Research (ICR)) , Ambroise Desfosses (University Grenoble Alpes, CEA, CNRS) , Paul C. R. Hopkins (The Institute of Cancer Research (ICR)) , Catherine M. Templeton (The Institute of Cancer Research (ICR)) , Fabienne Beuron (The Institute of Cancer Research) , Edward P. Morris (The Institute of Cancer Research (ICR)) , Sebastian Guettler (The Institute of Cancer Research (ICR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 20

State: Published (Approved)
Published: November 2022
Diamond Proposal Number(s): 28549 , 15624 , 16822 , 16023 , 21809

Open Access Open Access

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.

Journal Keywords: Cryoelectron microscopy; Intracellular signalling peptides and proteins; PolyADP-ribosylation; Transferases

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond , Krios II-Titan Krios II at Diamond , Krios III-Titan Krios III at Diamond

Added On: 28/11/2022 09:24

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)