5JRT

Crystal structure of the human Tankyrase 2 (TNKS2) SAM domain (DH902/924RE)

Summary for 5JRT

• Entry DOI: 10.2210/pdb5jrt/pdb
• Descriptor: Tankyrase-2 (2 entities in total)
• Functional Keywords: tankyrase polymerisation wnt signalling poly(adp-ribose)polymerase (parp), transferase, signalling protein, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 1
• Total formula weight: 8801.16

Authors

Guettler, S.,Mariotti, L.,Cronin, N. (deposition date: 2016-05-06, release date: 2016-08-03, Last modification date: 2024-05-01)

Primary citation

Mariotti, L.,Templeton, C.M.,Ranes, M.,Paracuellos, P.,Cronin, N.,Beuron, F.,Morris, E.,Guettler, S.
Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-beta-Catenin Signaling.
Mol.Cell, 63:498-513, 2016

PubMed 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.

PubMed: 27494558
DOI: 10.1016/j.molcel.2016.06.019

Experimental method

X-RAY DIFFRACTION (1.53 Å)