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 and Sebastian Guettler ()
Additional contact information
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 (ICR)
Edward P. Morris: The Institute of Cancer Research (ICR)
Sebastian Guettler: The Institute of Cancer Research (ICR)

Nature, 2022, vol. 612, issue 7938, 162-169

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 polymerization3–5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05449-8

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