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Structural insights into SAM domain-mediated tankyrase oligomerization
Paul A DaRosa1,2, Sergey Ovchinnikov1,3, Wenqing Xu2
1Department of Biochemistry, University of Washington, Seattle, Washington, 98195.
Protein Science : a Publication of the Protein Society
|June 22, 2016
Summary
Tankyrase proteins (TNKS) self-associate via helical polymers of their sterile alpha motif (SAM) domains. This structural insight enables the creation of soluble TNKS proteins for further study.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) are homologous poly(ADP-ribose) polymerases (PARPs) involved in critical cellular processes.
- These proteins possess a sterile alpha motif (SAM) domain implicated in oligomerization, but its structure and oligomerization mode remain uncharacterized.
Purpose of the Study:
- To structurally model the SAM domain-mediated oligomerization of tankyrases.
- To investigate the formation of homo- and hetero-oligomeric structures between TNKS1 and TNKS2.
- To generate soluble TNKS proteins through targeted mutations.
Main Methods:
- Computational modeling of the TNKS SAM domain oligomerization.
- Site-directed mutagenesis to probe the SAM oligomerization interface.
- Nuclear Magnetic Resonance (NMR) analysis to support structural findings.
Main Results:
- A helical, head-to-tail polymer model for TNKS SAM domain-mediated self-association was proposed.
- Evidence for the formation of (TNKS1 SAM-TNKS2 SAM) hetero-oligomeric structures was demonstrated.
- Mutations at the SAM oligomerization interface yielded soluble TNKS proteins, overcoming wild-type insolubility.
Conclusions:
- Structural characterization of TNKS SAM domain oligomerization provides a foundation for understanding TNKS function.
- The ability to generate soluble TNKS proteins facilitates further biophysical and functional studies.
- These findings are crucial for elucidating the role of TNKS oligomerization in PARylation and ubiquitylation processes.
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