The Transition of Photoreceptor Guanylate Cyclase Type 1 to the Active State

Shahu, Manisha Kumari; Schuhmann, Fabian; Scholten, Alexander; Solov’yov, Ilia A.; Koch, Karl‐Wilhelm

doi:10.3390/ijms23074030

Cited by 4 publications

(1 citation statement)

References 51 publications

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“…Two disulfide bridged cysteine residues act as a transduction node (TN) to guide the transmembrane migration of the ANF signal to an intracellular, ATP-Regulated Module (ARM; Duda et al, 2005b ). Significantly, the TN is active only in the hormone receptor guanylate cyclases but not in the photoreceptor guanylate cyclases ( Shahu et al, 2022 ). ATP amplifies the ANF signal by bringing two critical domains to the surface: a glycine rich cluster G-X-G 505 -X-X-X-G, making surrounding serine and threonine available for phosphorylation (GRC-P) and a 7-aa residue W 669 -TAPELL 675 motif to activate the core catalytic domain (CCD).…”

Section: Hormonally-modulated Mgc Signal-transduction Pathwaymentioning

confidence: 99%

Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder

Duda

Sharma

2023

Front. Mol. Neurosci.

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One monumental discovery in the field of cell biology is the establishment of the membrane guanylate cyclase signal transduction system. Decoding its fundamental, molecular, biochemical, and genetic features revolutionized the processes of developing therapies for diseases of endocrinology, cardio-vasculature, and sensory neurons; lastly, it has started to leave its imprints with the atmospheric carbon dioxide. The membrane guanylate cyclase does so via its multi-limbed structure. The inter-netted limbs throughout the central, sympathetic, and parasympathetic systems perform these functions. They generate their common second messenger, cyclic GMP to affect the physiology. This review describes an historical account of their sequential evolutionary development, their structural components and their mechanisms of interaction. The foundational principles were laid down by the discovery of its first limb, the ACTH modulated signaling pathway (the companion monograph). It challenged two general existing dogmas at the time. First, there was the question of the existence of a membrane guanylate cyclase independent from a soluble form that was heme-regulated. Second, the sole known cyclic AMP three-component-transduction system was modulated by GTP-binding proteins, so there was the question of whether a one-component transduction system could exclusively modulate cyclic GMP in response to the polypeptide hormone, ACTH. The present review moves past the first question and narrates the evolution and complexity of the cyclic GMP signaling pathway. Besides ACTH, there are at least five additional limbs. Each embodies a unique modular design to perform a specific physiological function; exemplified by ATP binding and phosphorylation, Ca2+-sensor proteins that either increase or decrease cyclic GMP synthesis, co-expression of antithetical Ca2+ sensors, GCAP1 and S100B, and modulation by atmospheric carbon dioxide and temperature. The complexity provided by these various manners of operation enables membrane guanylate cyclase to conduct diverse functions, exemplified by the control over cardiovasculature, sensory neurons and, endocrine systems.

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Section: Hormonally-modulated Mgc Signal-transduction Pathwaymentioning

confidence: 99%

Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder

Duda

Sharma

2023

Front. Mol. Neurosci.

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Different receptor models show differences in ligand binding strength and location: a computational drug screening for the tick-borne encephalitis virus

Finke,

Hungerland,

Solov’yov

et al. 2024

Mol Divers

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The tick-borne encephalitis virus (TBE) is a neurotrophic disease that has spread more rapidly throughout Europe and Asia in the past few years. At the same time, no cure or specific therapy is known to battle the illness apart from vaccination. To find a pharmacologically relevant drug, a computer-aided drug screening was initiated. Such a procedure probes a possible binding of a drug to the RNA Polymerase of TBE. The crystal structure of the receptor, however, includes missing and partially modeled regions, which rendered the structure incomplete and of questionable use for a thorough drug screening procedure. The quality of the receptor model was addressed by studying three putative structures created. We show that the choice of receptor models greatly influences the binding affinity of potential drug molecules and that the binding location could also be significantly impacted. We demonstrate that some drug candidates are unsuitable for one model but show decent results for another. Without any prejudice on the three employed receptor models, the study reveals the imperative need to investigate the receptor structure before drug binding is probed whether experimentally or computationally.

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Allosteric Communication of the Dimerization and the Catalytic Domain in Photoreceptor Guanylate Cyclase

Shahu,

Schuhmann,

Wong

et al. 2024

Biochemistry

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Phototransduction in vertebrate photoreceptor cells is controlled by Ca 2+ -dependent feedback loops involving the membrane-bound guanylate cyclase GC-E that synthesizes the second messenger guanosine-3′,5′-cyclic monophosphate. Intracellular Ca 2+ -sensor proteins named guanylate cyclase-activating proteins (GCAPs) regulate the activity of GC-E by switching from a Ca 2+ -bound inhibiting state to a Ca 2+ -free/Mg 2+ -bound activating state. The gene GUCY2D encodes for human GC-E, and mutations in GUCY2D are often associated with an imbalance of Ca 2+ and cGMP homeostasis causing retinal disorders. Here, we investigate the Ca 2+ -dependent inhibition of the constitutively active GC-E mutant V902L. The inhibition is not mediated by GCAP variants but by Ca 2+ replacing Mg 2+ in the catalytic center. Distant from the cyclase catalytic domain is an α-helical domain containing a highly conserved helix-turn-helix motif. Mutating the critical amino acid position 804 from leucine to proline left the principal activation mechanism intact but resulted in a lower level of catalytic efficiency. Our experimental analysis of amino acid positions in two distant GC-E domains implied an allosteric communication pathway connecting the α-helical and the cyclase catalytic domains. A computational connectivity analysis unveiled critical differences between wildtype GC-E and the mutant V902L in the allosteric network of critical amino acid positions.

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The Transition of Photoreceptor Guanylate Cyclase Type 1 to the Active State

Cited by 4 publications

References 51 publications

Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder

Multilimbed membrane guanylate cyclase signaling system, evolutionary ladder

Different receptor models show differences in ligand binding strength and location: a computational drug screening for the tick-borne encephalitis virus

Allosteric Communication of the Dimerization and the Catalytic Domain in Photoreceptor Guanylate Cyclase

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