TY - JOUR
T1 - It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods
AU - Qureshi, Bilal M.
AU - Behrmann, Elmar
AU - Schöneberg, Johannes
AU - Loerke, Justus
AU - Bürger, Jörg
AU - Mielke, Thorsten
AU - Giesebrecht, Jan
AU - Noé, Frank
AU - Lamb, Trevor D.
AU - Hofmann, Klaus Peter
AU - Spahn, Christian M. T.
AU - Heck, Martin
N1 - KAUST Repository Item: Exported on 2021-02-19
Acknowledgements: This 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.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10754/628786
UR - http://rsob.royalsocietypublishing.org/content/8/8/180075
UR - http://www.scopus.com/inward/record.url?scp=85053147038&partnerID=8YFLogxK
U2 - 10.1098/rsob.180075
DO - 10.1098/rsob.180075
M3 - Article
AN - SCOPUS:85053147038
VL - 8
SP - 180075
JO - Open Biology
JF - Open Biology
SN - 2046-2441
IS - 8
ER -