Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Qureshi, Bilal M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Behrmann, Elmar UNSPECIFIED orcid.org/0000-0001-6794-3669 UNSPECIFIED Schoeneberg, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Loerke, Justus UNSPECIFIED UNSPECIFIED UNSPECIFIED Buerger, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Mielke, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Giesebrecht, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Noe, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Lamb, Trevor D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Klaus Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Spahn, Christian M. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heck, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language CYCLIC-GMP PHOSPHODIESTERASE; G-PROTEIN EFFECTOR; GAMMA-SUBUNIT; NUCLEOTIDE PHOSPHODIESTERASES; OUTER SEGMENTS; GAF DOMAINS; DARK NOISE; BOVINE; BINDING; MECHANISM Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17810