In search of a function for the membrane anchors of class IIIa adenylate cyclases

Finkbeiner, Manuel; Grischin, Julia; Seth, Anubha; Schultz, Joachim E.

doi:10.1016/j.ijmm.2019.03.006

Cited by 7 publications

(3 citation statements)

References 35 publications

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“…Although full-length AC9 is resistant to regulation by G proteins, the interfaced helices 6 and 12 of the transmembrane arrays continue into the cytoplasm as the transducing helices and form the coiled-coil ( Qi et al, 2019 ). The transmembrane arrays may function as cell-surface receptors and/or sensors of the lipid composition of the plasma membrane, and changes in the relative positions of helices 6 and 12 may be transmitted to the coiled-coil ( Finkbeiner et al, 2019 ; Qi et al, 2019 , 2022 ; Seth et al, 2020 ). Overall, this scenario appears similar to the activation of soluble guanylyl cyclase by nitric oxide ( Horst et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain

Chen

Antoni

2023

Life Sci. Alliance

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Human transmembrane adenylyl cyclase 9 (AC9) is not regulated by heterotrimeric G proteins. Key to the resistance to stimulation by Gs-coupled receptors (GsRs) is auto-inhibition by the COOH-terminal domain (C2b). The present study investigated the role of the C2b domain in the regulation of cyclic AMP production by AC9 in HEK293FT cells expressing the GloSensor22F cyclic AMP-reporter protein. Surprisingly, we found C2b to be essential for sustaining the basal output of cyclic AMP by AC9. A human mutation (E326D) in the parallel coiled-coil formed by the signalling helices of AC9 dramatically increased basal activity, which was also dependent on the C2b domain. Intriguingly, the same mutation enabled stimulation of AC9 by GsRs. In summary, auto-regulation by the C2b domain of AC9 sustains its basal activity and quenches activation by GsR. Thus, AC9 appears to be tailored to support constitutive activation of cyclic AMP effector systems. A switch from this paradigm to stimulation by GsRs may be occasioned by conformational changes at the coiled-coil or removal of the C2b domain.

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Section: Resultsmentioning

confidence: 99%

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain

Chen

Antoni

2023

Life Sci. Alliance

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“…Conformation changes of the coiled-coil could occur under physiological conditions. While fulllength AC9 is resistant to regulation by G-proteins, the trans-membrane arrays may function as cell-surface receptors and/or sensors of the lipid composition of the plasma membrane (Finkbeiner et al , 2019; Qi et al ., 2022; Qi et al ., 2019; Seth et al , 2020). The interfaced helices 6 and 12 of the trans-membrane arrays continue into the cytoplasm as the transducing helices and form the coiled-coil (Qi et al ., 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Overall, this scenario is similar to the activation of soluble guanylyl cyclase by NO 8 . However, in the case of AC9 the transmembrane domains could function as cell-surface receptors and/or sensors of the lipid composition of the plasma membrane 3,4,32,33 . With respect to protein phosphorylation, functionally relevant activation of AC9 by protein kinase cascades independently of Gs has been reported in neutrophil granulocytes 34 .…”

Section: Discussionmentioning

confidence: 99%

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain and equipped with paradigm-switching mechanisms

Chen

Antoni

2022

Preprint

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Transmembrane adenylyl cyclase 9 (AC9) is unusual in not being regulated by heterotrimeric G proteins. The key to resistance to stimulation by Gs-coupled receptors (GsR) is auto-inhibition by the COOH-terminal domain (C2b). Surprisingly, we found C2b to be essential in sustaining the high basal output of cyclic AMP by AC9, which is regulated by intracellular free Ca2+ and calcineurin. A human mutation (E326D) in the parallel coiled-coil formed by the signalling helices of AC9 dramatically increased basal activity, which was dependent on the C2b domain. Intriguingly, the same mutation enabled stimulation of AC9 by GsRs. In summary, the C2b domain of AC9 sustains its basal activity (auto-stimulation) and quenches activation by GsR (auto-inhibition). Thus AC9 is tailored to support constitutive phosphorylation by protein kinase A. A switch from this paradigm to stimulation by GsRs may be occasioned by conformation changes at the coiled-coil or removal of the C2b domain.

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Cyclic di-GMP Signaling in Extreme Acidophilic Bacteria

Castro

Díaz

Beltrán

et al. 2020

Microbial Cyclic Di-Nucleotide Signaling

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In search of a function for the membrane anchors of class IIIa adenylate cyclases

Cited by 7 publications

References 35 publications

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain

Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain and equipped with paradigm-switching mechanisms

Cyclic di-GMP Signaling in Extreme Acidophilic Bacteria

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