The discovery of hidden guanylate cyclases (GCs) in the Homo sapiens proteome

Ilona Turek; Lubna Freihat; Jignesh Vyas; Janet Wheeler; Victor Muleya; David T Manallack; Chris Gehring; Helen Irving

doi:10.1016/j.csbj.2023.11.005

The discovery of hidden guanylate cyclases (GCs) in the Homo sapiens proteome

Comput Struct Biotechnol J. 2023 Nov 4:21:5523-5529. doi: 10.1016/j.csbj.2023.11.005. eCollection 2023.

Authors

Ilona Turek^{1

2}, Lubna Freihat³, Jignesh Vyas³, Janet Wheeler^{3

4}, Victor Muleya³, David T Manallack⁵, Chris Gehring⁶, Helen Irving^{1

2

3}

Affiliations

¹ La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia.
² Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo, VIC 3550, Australia.
³ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
⁴ Department of Animal, Plant and Soil Science, La Trobe University, AgriBio building, Bundoora, VIC 3086, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
⁶ Department of Chemistry, Biochemistry and Biotechnology, University of Perugia, 06121 Perugia, Italy.

Abstract

Recent discoveries have established functional guanylate cyclase (GC) catalytic centers with low activity within kinase domains in plants. These crypto GCs generate guanosine 3',5'-cyclic monophosphate (cGMP) essential for both intramolecular and downstream signaling. Here, we have set out to search for such crypto GCs moonlighting in kinases in the H. sapiens proteome and identified 18 candidates, including the neurotropic receptor tyrosine kinase 1 (NTRK1). NTRK1 shows a domain architecture much like plant receptor kinases such as the phytosulfokine receptor, where a functional GC essential for downstream signaling is embedded within a kinase domain. In vitro characterization of the NTRK1 shows that the embedded NTRK1 GC is functional with a marked preference for Mn²⁺ over Mg²⁺. This therefore points to hitherto unsuspected roles of cGMP in intramolecular and downstream signaling of NTRK1 and the role of cGMP in NTRK1-dependent growth and neoplasia.

Keywords: Crypto guanylate cyclase; Cyclic GMP (cGMP); Neurotropic receptor tyrosine kinase 1 (NTRK1); Phytosulfokine receptor 1 (PSKR1); Tyrosine receptor kinase A (TrkA).