Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Signaling

Background:

• Tankyrase (TNKS and TNKS2) are poly(ADP-ribose) polymerase enzymes crucial for Wnt-β-catenin signaling.
• Tankyrase destabilizes AXIN, a scaffolding protein essential for regulating β-catenin levels.
• The polymerization ability of Tankyrase and its functional relevance were previously unclear.

Purpose of the Study:

• To elucidate the structural basis and functional significance of Tankyrase polymerization.
• To investigate how Tankyrase polymerization impacts its enzymatic activity and interaction with AXIN.
• To explore novel therapeutic strategies targeting Tankyrase in Wnt-dependent cancers.

Main Methods:

• X-ray crystallography to determine the structures of TNKS and TNKS2 SAM domains.
• Biochemical assays to assess Tankyrase polymerization and PARP activity.
• Analysis of Tankyrase's interaction with AXIN and its role in β-catenin signaling.

Main Results:

• Crystal structures reveal head-to-tail polymerization of TNKS and TNKS2 SAM domains.
• Tankyrase polymerization is required for driving β-catenin-dependent transcription.
• The polymeric state enhances PARP activity and facilitates avidity-dependent AXIN binding.
• This polymerization mechanism is crucial for regulating signal transduction in signalosomes.

Conclusions:

• Tankyrase polymerization is a critical regulatory mechanism for Wnt signaling.
• The polymeric state enables Tankyrase to effectively target destruction complexes.
• Targeting Tankyrase polymerization offers a promising strategy for inhibiting oncogenic Wnt signaling.