Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
Open accessAbstract
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.
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DNMDP and related small molecules induce interaction between PDE3A and SLFN12, leading to a cytotoxic effect in cancer cells with high expression of both proteins.
“DNMDP and related small molecules induce interaction between the phosphodiesterase PDE3A and SLFN12 (Fig. 3C and 6), leading to a cytotoxic effect in cancer cells with high expression of both proteins.75,105”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [75]
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References 47 · Cited by 85
- Authors
- Garvie, C. W., Wu, X., Papanastasiou, M., Lee, S., Fuller, J., Schnitzler, G. R., Horner, S. W., Baker, A., Zhang, T., Mullahoo, J. P., Westlake, L., Hoyt, S. H., Toetzl, M., Ranaghan, M. J., de Waal, L., McGaunn, J., Kaplan, B., Piccioni, F., Yang, X., Lange, M., Tersteegen, A., Raymond, D., Lewis, T. A., Carr, S. A., Cherniack, A. D., Lemke, C. T., Meyerson, M., & Greulich, H.
- Affiliations
- Broad Institute (US)
- Helix Biostructures (United States) (US)
- Bayer (Germany) (DE)
- Corresponding author
- Greulich, Heidi
- ORCID
- Garvie, Colin W.
- Wu, Xiaoyun
- Papanastasiou, Malvina
- Fuller, James
- Horner, Steven W.
- Mullahoo, James P.
- Hoyt, Stephanie H.
- Ranaghan, Matthew J.
- McGaunn, Joseph
- Kaplan, Bethany
- Piccioni, Federica
- Yang, Xiaoping
- Lange, Martin
- Raymond, Donald
- Lewis, Timothy A.
- Carr, Steven A.
- Cherniack, Andrew D.
- Lemke, Christopher T.
- Meyerson, Matthew
- Greulich, Heidi
- Venue
- Nature Communications
- Published
- 2021-07-16
- Volume
- 12
- Issue
- 1
- Pages
- 4375-4375
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8285493
- OpenAlex
- W3181471647
- Cited by
- 85
- References
- 47
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 19 · 2023: 18 · 2022: 11 · 2021: 6
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Bayer AG Broad Institute Next Generation Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- PDE3A, SLFN12, heterotetramer, protein complex structure, ribonuclease activity, cancer cell death, C-terminal alpha-helix, active site binding, anticancer drug development
- MeSH terms
- Protein Conformation, alpha-Helical, Adenosine Monophosphate, Calorimetry, Differential Scanning, Cell Survival, Endoribonucleases, HeLa Cells, Humans, Kinetics, Multienzyme Complexes, Mutation, Protein Binding, Pyridazines, Recombinant Proteins, Mass Spectrometry, Catalytic Domain, Cryoelectron Microscopy, Tetrahydroisoquinolines, Intracellular Signaling Peptides and Proteins, Cyclic Nucleotide Phosphodiesterases, Type 3, Protein Multimerization, HEK293 Cells
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