Qureshi, Bilal M., Behrmann, Elmar ORCID: 0000-0001-6794-3669, Schoeneberg, Johannes, Loerke, Justus, Buerger, Joerg, Mielke, Thorsten, Giesebrecht, Jan, Noe, Frank, Lamb, Trevor D., Hofmann, Klaus Peter, Spahn, Christian M. T. and Heck, Martin (2018). It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods. Open Biol, 8 (8). LONDON: ROYAL SOC. ISSN 2046-2441

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Abstract

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 alpha-subunits (G alpha*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. G alpha* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of G alpha* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 G alpha*. PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that G alpha*. PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of G alpha* which binds with lower affinity, forming G alpha*. PDE6. G alpha*. 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 G alpha* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated G alpha* fails to activate the effector enzyme.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Qureshi, Bilal M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrmann, ElmarUNSPECIFIEDorcid.org/0000-0001-6794-3669UNSPECIFIED
Schoeneberg, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loerke, JustusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buerger, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mielke, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giesebrecht, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noe, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamb, Trevor D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, Klaus PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spahn, Christian M. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heck, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-178105
DOI: 10.1098/rsob.180075
Journal or Publication Title: Open Biol
Volume: 8
Number: 8
Date: 2018
Publisher: ROYAL SOC
Place of Publication: LONDON
ISSN: 2046-2441
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CYCLIC-GMP PHOSPHODIESTERASE; G-PROTEIN EFFECTOR; GAMMA-SUBUNIT; NUCLEOTIDE PHOSPHODIESTERASES; OUTER SEGMENTS; GAF DOMAINS; DARK NOISE; BOVINE; BINDING; MECHANISMMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17810

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