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

Nat Commun. 2021 Jul 16;12(1):4375. doi: 10.1038/s41467-021-24495-w.

Colin W Garvie ^# ¹, Xiaoyun Wu ^# ², Malvina Papanastasiou ³, Sooncheol Lee ², James Fuller ⁴, Gavin R Schnitzler ², Steven W Horner ¹, Andrew Baker ², Terry Zhang ⁵, James P Mullahoo ³, Lindsay Westlake ², Stephanie H Hoyt ², Marcus Toetzl ², Matthew J Ranaghan ¹, Luc de Waal ², Joseph McGaunn ², Bethany Kaplan ², Federica Piccioni ⁶ ⁷, Xiaoping Yang ⁶, Martin Lange ⁸ ⁹, Adrian Tersteegen ¹⁰, Donald Raymond ¹, Timothy A Lewis ¹, Steven A Carr ³, Andrew D Cherniack ² ¹¹, Christopher T Lemke ¹, Matthew Meyerson ² ¹¹, Heidi Greulich ¹² ¹³

Affiliations

1 Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3 Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4 Helix Biostructures, Indianapolis, IN, USA.
5 Thermo Fisher, San Jose, CA, USA.
6 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7 Merck Research Laboratories, Boston, MA, USA.
8 Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany.
9 NUVISAN ICB GmbH, Berlin, Germany.
10 Research and Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.
11 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
12 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
13 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
# Contributed equally.

PMID: 34272366 DOI: 10.1038/s41467-021-24495-w

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.

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