Structural basis of tankyrase activation by polymerization.
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Embargo End Date
Authors
Pillay, N
Mariotti, L
Zaleska, M
Inian, O
Jessop, M
Hibbs, S
Desfosses, A
Hopkins, PCR
Templeton, CM
Beuron, F
Morris, EP
Guettler, S
Mariotti, L
Zaleska, M
Inian, O
Jessop, M
Hibbs, S
Desfosses, A
Hopkins, PCR
Templeton, CM
Beuron, F
Morris, EP
Guettler, S
Document Type
Journal Article
Date
2022-12-01
Date Accepted
2022-10-13
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.
Citation
Nature, 2022, 612 (7938), pp. 162 - 169
Source Title
Nature
Publisher
NATURE PORTFOLIO
ISSN
0028-0836
eISSN
1476-4687
1476-4687
1476-4687
Collections
Research Team
Electron Microscopy Fac
Struct Electron Microsc
Struct Biol Cell Signal
Struct Electron Microsc
Struct Biol Cell Signal