It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods
AuthorsQureshi, Bilal M.
Lamb, Trevor D.
Hofmann, Klaus Peter
Spahn, Christian M. T.
Online Publication Date2018-08
Print Publication Date2018-08
Permanent link to this recordhttp://hdl.handle.net/10754/628786
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AbstractAmong cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein α-subunits (Gα∗). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. Gα∗ titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of Gα∗ for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1: 1 Gα∗ · PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that Gα∗ · PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of Gα∗ which binds with lower affinity, forming Gα∗ · PDE6 · Gα∗. Reaction-diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of Gα∗ generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated Gα∗ fails to activate the effector enzyme.
CitationQureshi BM, Behrmann E, Schöneberg J, Loerke J, Bürger J, et al. (2018) It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods. Open Biology 8: 180075. Available: http://dx.doi.org/10.1098/rsob.180075.
SponsorsThis work was funded by Deutsche Forschungsgemeinschaft through grant nos. SP 1130/1-1 and SFB 449 to M.H., K.P.H. and C.M.T.S., SFB 740 to F.N., M.H., K.P.H., T.M. and C.M.T.S., a European Research Council starting grant (pcCell) to F.N. and a European Research Council advanced grant (TUDOR) to K.P.H. E.B. holds a Freigeist-Fellowship from the Volkswagen Foundation.
PublisherThe Royal Society
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Qureshi, B. M., Behrmann, E., Schöneberg, J., Loerke, J., Bürger, J., Mielke, T., Giesebrecht, J., Noé, F., Lamb, T. D., Hofmann, K. P., Spahn, C. M. T., & Heck, M. (2018). Supplementary material from "It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods". Figshare. https://doi.org/10.6084/M9.FIGSHARE.C.4170272.V2. DOI: 10.6084/m9.figshare.c.4170272.v2 Handle: 10754/664191
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