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

Author

Listed:
  • 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
    Merck Research Laboratories)

  • Xiaoping Yang

    (Broad Institute of MIT and Harvard)

  • Martin Lange

    (Pharmaceuticals, Bayer AG
    NUVISAN ICB GmbH)

  • 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
    Dana-Farber Cancer Institute)

  • Christopher T. Lemke

    (Broad Institute of MIT and Harvard)

  • Matthew Meyerson

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Heidi Greulich

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

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.

Suggested Citation

  • 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 & Steph, 2021. "Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24495-w
    DOI: 10.1038/s41467-021-24495-w
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    Cited by:

    1. Felix J. Metzner & Simon J. Wenzl & Michael Kugler & Stefan Krebs & Karl-Peter Hopfner & Katja Lammens, 2022. "Mechanistic understanding of human SLFN11," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Andrew Muenks & Samantha Zepeda & Guangfeng Zhou & David Veesler & Frank DiMaio, 2023. "Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Jie Chen & Nan Liu & Yinpin Huang & Yuanxun Wang & Yuxing Sun & Qingcui Wu & Dianrong Li & Shuanhu Gao & Hong-Wei Wang & Niu Huang & Xiangbing Qi & Xiaodong Wang, 2021. "Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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