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Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease
Sebastian Guettler1, Jose LaRose, Evangelia Petsalaki
1Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Cell
|December 14, 2011
Summary
Researchers uncovered the binding rules for Tankyrase enzymes (TNKS/TNKS2), crucial for protein regulation and linked to cherubism. This discovery clarifies how Tankyrases recognize substrates and explains disease mutations.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Tankyrase 1/2 (TNKS/TNKS2) are enzymes catalyzing ADP-ribosylation, impacting protein ubiquitylation, stability, and function.
- Dysregulation of TNKS substrate recognition is implicated in the human disease cherubism.
- TNKS enzymes utilize ankyrin repeat clusters (ARCs) to bind specific substrate motifs (RxxPDG hexapeptides).
Purpose of the Study:
- To determine the structural basis of Tankyrase substrate recognition.
- To derive a consensus sequence for TNKS substrate binding across conserved ARCs.
- To rationalize known TNKS substrates and explain cherubism-related mutations.
Main Methods:
- Crystal structures of a TNKS2 ankyrin repeat cluster (ARC) bound to six substrate peptides.
- Solution-based peptide library screening to identify substrate consensus sequences.
- Bioinformatic analysis and experimental validation of predicted TNKS targets.
Main Results:
- Reported crystal structures of a representative TNKS2 ARC bound to six distinct substrate peptides.
- Derived an 8-residue consensus sequence for TNKS substrate recognition common to four conserved ARCs.
- Rationalized all known TNKS substrates and explained cherubism mutations in the 3BP2 substrate.
- Predicted and validated additional TNKS targets, including Disc1, Striatin, Fat4, RAD54, BCR, and MERIT40.
Conclusions:
- Established a rule-based consensus for Tankyrase substrate binding, enhancing understanding of TNKS function.
- Provided structural insights into how TNKS enzymes recognize and bind substrates via ARCs.
- The findings offer a foundation for understanding cherubism pathogenesis and identifying new therapeutic targets.
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