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Medientyp:
E-Artikel
Titel:
It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods
Beteiligte:
Qureshi, Bilal M.;
Behrmann, Elmar;
Schöneberg, Johannes;
Loerke, Justus;
Bürger, Jörg;
Mielke, Thorsten;
Giesebrecht, Jan;
Noé, Frank;
Lamb, Trevor D.;
Hofmann, Klaus Peter;
Spahn, Christian M. T.;
Heck, Martin
Erschienen:
The Royal Society, 2018
Erschienen in:Open Biology
Sprache:
Englisch
DOI:
10.1098/rsob.180075
ISSN:
2046-2441
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>Among 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.</jats:p>