Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase

Colin W. Garvie, Xiaoyun Wu, Malvina Papanastasiou, Sooncheol Lee, James Fuller, Gavin R. Schnitzler, Steven W. Horner, Andrew Baker, Terry Zhang, James P. Mullahoo, Lindsay Westlake, Stephanie H. Hoyt, Marcus Toetzl, Matthew J. Ranaghan, Luc Waal, Joseph McGaunn, Bethany Kaplan, Federica Piccioni, Xiaoping Yang, Martin Lange, Adrian Tersteegen, Donald Raymond, Timothy A. Lewis, Steven A. Carr, Andrew D. Cherniack, Christopher T. Lemke, Matthew Meyerson and Heidi Greulich ()
Additional contact information
Colin W. Garvie: Broad Institute of MIT and Harvard
Xiaoyun Wu: Broad Institute of MIT and Harvard
Malvina Papanastasiou: Broad Institute of MIT and Harvard
Sooncheol Lee: Broad Institute of MIT and Harvard
James Fuller: Helix Biostructures
Gavin R. Schnitzler: Broad Institute of MIT and Harvard
Steven W. Horner: Broad Institute of MIT and Harvard
Andrew Baker: Broad Institute of MIT and Harvard
Terry Zhang: Thermo Fisher
James P. Mullahoo: Broad Institute of MIT and Harvard
Lindsay Westlake: Broad Institute of MIT and Harvard
Stephanie H. Hoyt: Broad Institute of MIT and Harvard
Marcus Toetzl: Broad Institute of MIT and Harvard
Matthew J. Ranaghan: Broad Institute of MIT and Harvard
Luc Waal: Broad Institute of MIT and Harvard
Joseph McGaunn: Broad Institute of MIT and Harvard
Bethany Kaplan: Broad Institute of MIT and Harvard
Federica Piccioni: Broad Institute of MIT and Harvard
Xiaoping Yang: Broad Institute of MIT and Harvard
Martin Lange: Pharmaceuticals, Bayer AG
Adrian Tersteegen: Pharmaceuticals, Bayer AG
Donald Raymond: Broad Institute of MIT and Harvard
Timothy A. Lewis: Broad Institute of MIT and Harvard
Steven A. Carr: Broad Institute of MIT and Harvard
Andrew D. Cherniack: Broad Institute of MIT and Harvard
Christopher T. Lemke: Broad Institute of MIT and Harvard
Matthew Meyerson: Broad Institute of MIT and Harvard
Heidi Greulich: Broad Institute of MIT and Harvard

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.

Date: 2021
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DOI: 10.1038/s41467-021-24495-w

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