Comparison of moonlighting guanylate cyclases: Roles in signal direction?

Lubna Freihat, Victor Muleya, David Thomas Manallack, Janet Wheeler, Helen Ruth Irving

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Over 30 receptor-like kinases contain a guanylate cyclase (GC) catalytic centre embedded within the Cterminal region of their kinase domain in the model plant Arabidopsis. A number of the kinase GCs contain both functional kinase and GC activity in vitro and the natural ligands of these receptors stimulate increases in cGMP within isolated protoplasts. The GC activity could be described as a minor or moonlighting activity. We have also identified mammalian proteins that contain the novel GC centre embedded within kinase domains. One example is the interleukin 1 receptor-associated kinase 3 (IRAK3).We compare the GC functionality of the mammalian protein IRAK3 with the cytoplasmic domain of the plant prototype molecule, the phytosulfokine receptor 1 (PSKR1). We have developed homology models of these molecules and have undertaken in vitro experiments to compare their functionality and structural features. Recombinant IRAK3 produces cGMP at levels comparable to those produced by PSKR1, suggesting that IRAK3 contains GC activity. Our findings raise the possibility that kinase-GCs may switch between downstream kinase-mediated or cGMP-mediated signalling cascades to elicit desired outputs to particular stimuli. The challenge now lies in understanding the interaction between the GC and kinase domains and how these molecules utilize their dual functionality within cells.
Original languageEnglish
Pages (from-to)1773 - 1779
Number of pages7
JournalBiochemical Society Transactions
Volume42
DOIs
Publication statusPublished - 2014

Cite this

Freihat, Lubna ; Muleya, Victor ; Manallack, David Thomas ; Wheeler, Janet ; Irving, Helen Ruth. / Comparison of moonlighting guanylate cyclases: Roles in signal direction?. In: Biochemical Society Transactions. 2014 ; Vol. 42. pp. 1773 - 1779.
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Comparison of moonlighting guanylate cyclases: Roles in signal direction? / Freihat, Lubna; Muleya, Victor; Manallack, David Thomas; Wheeler, Janet; Irving, Helen Ruth.

In: Biochemical Society Transactions, Vol. 42, 2014, p. 1773 - 1779.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Comparison of moonlighting guanylate cyclases: Roles in signal direction?

AU - Freihat, Lubna

AU - Muleya, Victor

AU - Manallack, David Thomas

AU - Wheeler, Janet

AU - Irving, Helen Ruth

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AB - Over 30 receptor-like kinases contain a guanylate cyclase (GC) catalytic centre embedded within the Cterminal region of their kinase domain in the model plant Arabidopsis. A number of the kinase GCs contain both functional kinase and GC activity in vitro and the natural ligands of these receptors stimulate increases in cGMP within isolated protoplasts. The GC activity could be described as a minor or moonlighting activity. We have also identified mammalian proteins that contain the novel GC centre embedded within kinase domains. One example is the interleukin 1 receptor-associated kinase 3 (IRAK3).We compare the GC functionality of the mammalian protein IRAK3 with the cytoplasmic domain of the plant prototype molecule, the phytosulfokine receptor 1 (PSKR1). We have developed homology models of these molecules and have undertaken in vitro experiments to compare their functionality and structural features. Recombinant IRAK3 produces cGMP at levels comparable to those produced by PSKR1, suggesting that IRAK3 contains GC activity. Our findings raise the possibility that kinase-GCs may switch between downstream kinase-mediated or cGMP-mediated signalling cascades to elicit desired outputs to particular stimuli. The challenge now lies in understanding the interaction between the GC and kinase domains and how these molecules utilize their dual functionality within cells.

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