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

Computational and Structural Biotechnology Journal (Jan 2023)

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

Affiliations

Ilona Turek: La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo, VIC 3550, Australia
Lubna Freihat: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Jignesh Vyas: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Janet Wheeler: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Animal, Plant and Soil Science, La Trobe University, AgriBio building, Bundoora, VIC 3086, Australia
Victor Muleya: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
David T. Manallack: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Chris Gehring: Department of Chemistry, Biochemistry and Biotechnology, University of Perugia, 06121 Perugia, Italy
Helen Irving: La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, Bendigo, VIC 3550, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Corresponding author at: La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia.

Journal volume & issue: Vol. 21
pp. 5523 – 5529

Abstract

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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.

Published in Computational and Structural Biotechnology Journal

ISSN: 2001-0370 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Technology: Chemical technology: Biotechnology
Website: https://www.journals.elsevier.com/computational-and-structural-biotechnology-journal

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