cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A

Function

Cyclic nucleotide phosphodiesterase with specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Also has activity toward cUMP. Independently of its catalytic activity it is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling.

Classification

Family (Pfam)

PF00233 PDEase_I

InterPro

HD/PDEase_dom, PDEase_catalytic_dom, PDEase_catalytic_dom_sf, PDEase_CS

Functional cluster

RNA Polymerase II Transcription Factors

Experimental structures · PDB · 9

• 7EG0 EM 3.40A
• 7EG1 EM 3.20A
• 7EG4 EM 3.20A
• 7KWE X-ray 2.00A
• 7L27 X-ray 1.70A
• 7L28 X-ray 2.20A
• 7L29 X-ray 2.08A
• 7LRC EM 2.97A
• 7LRD EM 3.22A

A predicted model is available from AlphaFold.

Gene Ontology · 21

• GO:0005829 cytosol
• GO:0016020 membrane
• GO:0004119 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity
• GO:0004115 3',5'-cyclic-AMP phosphodiesterase activity
• GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity
• GO:0004114 3',5'-cyclic-nucleotide phosphodiesterase activity
• GO:0099130 estrogen binding
• GO:0046872 metal ion binding
• GO:0030284 nuclear estrogen receptor activity
• GO:0097190 apoptotic signaling pathway
• GO:0071321 cellular response to cGMP
• GO:0071560 cellular response to transforming growth factor beta stimulus
• GO:0007186 G protein-coupled receptor signaling pathway
• GO:0006629 lipid metabolic process
• GO:0106072 negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
• GO:0043066 negative regulation of apoptotic process
• GO:0141162 negative regulation of cAMP/PKA signal transduction
• GO:0043116 negative regulation of vascular permeability
• GO:0001556 oocyte maturation
• GO:0043117 positive regulation of vascular permeability
• GO:0060700 regulation of ribonuclease activity

Disease associations

• brachydactyly-arterial hypertension syndrome MONDO:0007211

Drugs targeting this protein · 16

• OXTRIPHYLLINE inhibitor
• THEOPHYLLINE SODIUM GLYCINATE inhibitor
• ANAGRELIDE HYDROCHLORIDE inhibitor
• MILRINONE LACTATE inhibitor
• THEOPHYLLINE inhibitor
• AMINOPHYLLINE inhibitor
• DYPHYLLINE inhibitor
• IBUDILAST inhibitor
• LEVOSIMENDAN inhibitor
• INAMRINONE LACTATE inhibitor
• ENOXIMONE inhibitor
• K-134 inhibitor
• ENSIFENTRINE inhibitor
• PENTOXIFYLLINE inhibitor
• CILOSTAZOL inhibitor
• DIPYRIDAMOLE inhibitor

Related proteins · sequence + function similarity

• cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A 0.97
• cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A 0.97
• cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B 0.92
• cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B 0.92
• cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B 0.91
• TBC1 domain family member 14 0.68
• TBC1 domain family member 14 0.67
• TBC1 domain family member 14 0.66
• TBC1 domain family member 12 0.65
• TBC1 domain family member 14 0.65
• Single-minded homolog 1-A 0.64
• Syntaphilin 0.64

Co-cited proteins · studied together in the literature

• Ribonuclease SLFN12 4 shared papers

Literature · 17 cited papers

• Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death. Cell Chem. Biol. · 2022
• Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells. Nat. Commun. · 2021
• Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nat. Commun. · 2021
• Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover. Mol. Cell · 2019
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• cUMP hydrolysis by PDE3A. Naunyn Schmiedebergs Arch. Pharmacol. · 2017
• PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat. Genet. · 2015
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
• Phosphoproteome of resting human platelets. J. Proteome Res. · 2008
• A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. · 2006
• … and 5 more in the literature graph