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Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate
- Source :
- Frontiers in Molecular Neuroscience, Frontiers in Molecular Neuroscience, Vol 10 (2017)
- Publication Year :
- 2017
- Publisher :
- Frontiers Media SA, 2017.
-
Abstract
- Membrane guanylate cyclase (MGC) is a ubiquitous multi-switching cyclic GMP generating signaling machine linked with countless physiological processes. In mammals it is encoded by seven distinct homologous genes. It is a single transmembrane spanning multi-modular protein; composed of integrated blocks and existing in homo-dimeric form. Its core catalytic domain (CCD) module is a common transduction center where all incoming signals are translated into the production of cyclic GMP, a cellular signal second messenger. Crystal structure of the MGC’s CCD does not exist and its precise identity is ill-defined. Here we define it at a sub-molecular level for the phototransduction-linked membrane guanylate cyclase, the rod outer segment guanylate cyclase type 1, ROS-GC1. (1) The CCD is a conserved 145-residue structural unit, represented by the segment V820-P964. (2) It exists as a homo-dimer and contains seven conserved catalytic elements (CEs) wedged into seven conserved motifs. (3) It also contains a conserved 21-residue neurocalcin δ-modulated structural domain, V836-L857. (4) Site-directed mutagenesis documents that each of the seven CEs governs the cyclase’s catalytic activity. (5) In contrast to the soluble and the bacterium membrane guanylate cyclase which use Mn2+-GTP substrate for catalysis, MGC CCD uses the natural Mg2+-GTP substrate. (6) Strikingly, the MGC CCD requires anchoring by the Transmembrane Domain (TMD) to exhibit its major (~92%) catalytic activity; in isolated form the activity is only marginal. This feature is not linked with any unique sequence of the TMD; there is minimal conservation in TMD. Finally, (7) the seven CEs control each of four phototransduction pathways- -two Ca2+-sensor GCAPs-, one Ca2+-sensor, S100B- and one bicarbonate-modulated. The findings disclose that the CCD of ROS-GC1 has built-in regulatory elements that control its signal translational activity. Due to conservation of these regulatory elements, it is proposed that these elements also control the physiological activity of other members of membrane guanylate cyclase family.
- Subjects :
- 0301 basic medicine
GUCY1B3
phototransduction
Cyclase
lcsh:RC321-571
03 medical and health sciences
Cellular and Molecular Neuroscience
cyclic GMP
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Molecular Biology
Original Research
GUCY1A2
Neurocalcin
biology
membrane guanylate cyclase
GUCY1A3
Transmembrane protein
Transmembrane domain
second messenger
030104 developmental biology
Biochemistry
Second messenger system
biology.protein
Biophysics
signal transduction
Neuroscience
Subjects
Details
- ISSN :
- 16625099
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Frontiers in Molecular Neuroscience
- Accession number :
- edsair.doi.dedup.....6c5c16ce66ed48fe3b69cfc8bc052871