Structural basis of tankyrase activation by polymerization.

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Cell Biology

Background:

• Tankyrase (TNKS) enzymes are key regulators of critical cellular pathways, including WNT signaling and DNA repair.
• Despite their importance in disease, the mechanisms controlling TNKS activity, particularly its polymerization, remain poorly understood.
• Understanding TNKS regulation is vital for developing targeted therapeutics.

Purpose of the Study:

• To elucidate the structural basis of tankyrase filamentous polymerization.
• To reveal how supramolecular assembly dictates both catalytic and non-catalytic functions of TNKS.
• To provide insights into the allosteric regulation of TNKS activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to reconstruct the structure of a minimal active TNKS filament.
• Analysis focused on the sterile alpha motif (SAM) and catalytic domains responsible for polymerization and activity.
• Structural data were correlated with functional assays in WNT-β-catenin signaling.

Main Results:

• A novel antiparallel double helix structure formed by the TNKS SAM domain was determined.
• This SAM domain arrangement positions catalytic domains for conserved head-to-head interactions, inducing allosteric activation.
• Tail-to-tail interactions, while less impactful on catalysis, are essential for WNT-β-catenin pathway function.

Conclusions:

• The study reveals a new mode of SAM domain polymerization controlling TNKS function.
• Supramolecular assembly is a critical determinant of both catalytic and non-catalytic roles of TNKS.
• These findings offer structural guidance for modulating TNKS activity in disease contexts.