Molecular Details of Retinal Guanylyl Cyclase 1/GCAP-2 Interaction

Rehkamp, Anne; Tänzler, Dirk; Iacobucci, Claudio; Golbik, Ralph; Ihling, Christian; Sinz, Andrea

doi:10.3389/fnmol.2018.00330

Cited by 11 publications

(6 citation statements)

References 52 publications

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“…While it is clear that both GCAPs can regulate GC1 over the narrow physiological window of intracellular Ca 2+ , quite different mechanisms have been proposed for the regulation. Some studies support distinct binding interfaces between GC1 and GCAP1/GCAP2, the first GCAP being located at the juxtamembrane region and the second prevalently bound to the catalytic-C terminal domain 29–31 , thus allowing the binding of GCAP1 and GCAP2 to either the same or distinct GC1 molecules, but always in different interfaces On the other hand, other studies found a partly overlapped GC interface for GCAP1 and GCAP2 32,33 , suggesting a competition between GCAP1 and GCAP2 for GC1 activation in mouse cones 34 as well as in rods. Overall, GCAPs seem to operate in a “calcium-relay” mode, thus acting simultaneously on either the same or distinct GC1 molecules to induce gradual responses in terms of cGMP synthesis triggered by small changes in intracellular [Ca 2+ ] 3,35 .…”

Section: Introductionmentioning

confidence: 99%

Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A

Dell’Orco

Cortivo

2019

Sci Rep

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Missense mutations in the GUCA1A gene encoding guanylate cyclase-activating protein 1 (GCAP1) are associated with autosomal dominant cone/cone-rod (CORD) dystrophies. The nature of the inheritance pattern implies that a pool of normal GCAP proteins is present in photoreceptors together with the mutated variant. To assess whether human GCAP1 and GCAP2 may similarly regulate the activity of the retinal membrane guanylate cyclase GC-1 (GC-E) in the presence of the recently discovered E111V-GCAP1 CORD-variant, we combined biochemical and in silico assays. Surprisingly, human GCAP2 does not activate GC1 over the physiological range of Ca2+ whereas wild-type GCAP1 significantly attenuates the dysregulation of GC1 induced by E111V-GCAP1. Simulation of the phototransduction cascade in a well-characterized murine system, where GCAP2 is able to activate the GC1, suggests that both GCAPs can act in a synergic manner to mitigate the effects of the CORD-mutation. We propose the existence of a species-dependent compensatory mechanism. In murine photoreceptors, slight increases of wild-type GCAPs levels may significantly attenuate the increase in intracellular Ca2+ and cGMP induced by E111V-GCAP1 in heterozygous conditions. In humans, however, the excess of wild-type GCAP1 may only partly attenuate the mutant-induced dysregulation of cGMP signaling due to the lack of GC1-regulation by GCAP2.

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Section: Introductionmentioning

confidence: 99%

Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A

Dell’Orco

Cortivo

2019

Sci Rep

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“…XLMS experiments on complex protein mixtures usually yield thousands of cross-links, making the inspection of individual spectra impossible. Recently, DSBU and MeroX have been combined for developing XLMS workflows to study isolated proteins or protein complexes. ,− …”

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confidence: 99%

A Simple Cross-Linking/Mass Spectrometry Workflow for Studying System-wide Protein Interactions

et al. 2019

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We present a cross-linking/mass spectrometry workflow for performing proteome-wide cross-linking analyses within 1 week. The workflow is based on the commercially available mass spectrometry-cleavable cross-linker disuccinimidyl dibutyric urea and can be employed by every lab having access to a mass spectrometer with tandem mass spectrometry capabilities. We provide an updated version 2.0 of the freeware software tool MeroX, available at , that allows us to conduct fully automated and reliable studies delivering insights into protein–protein interaction networks and protein conformations at the proteome level. We exemplify our optimized workflow for mapping protein–protein interaction networks in Drosophila melanogaster embryos on a system-wide level. From cross-linked Drosophila embryo extracts, we detected 29931 cross-link spectrum matches corresponding to 7436 unique cross-linked residues in biological triplicate experiments at a 1% false discovery rate. Among these, 1611 interprotein cross-linking sites were identified and yielded valuable information about protein–protein interactions. The 5825 remaining intraprotein cross-links yield information about the conformational landscape of proteins in their cellular environment.

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“…GMP − PDEα1 and/or GMP − PDEα2 convert cGMP to GMP which closes the CNG ion channel. Conversely, ANPR1-like and ANPR1-like2 [64, 65] convert GTP to cGMP helping to regulate the opening and closing of CNG. Finally, transduction is terminated by arrestin deactivating metarhodopsin and phosphorylation of metarhodopsin by Rh kinase and GRK5-like.…”

Section: Discussionmentioning

confidence: 99%

Molecular evolution and expression of opsin genes in Hydra vulgaris

2019

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BackgroundThe evolution of opsin genes is of great interest because it can provide insight into the evolution of light detection and vision. An interesting group in which to study opsins is Cnidaria because it is a basal phylum sister to Bilateria with much visual diversity within the phylum. Hydra vulgaris (H. vulgaris) is a cnidarian with a plethora of genomic resources to characterize the opsin gene family. This eyeless cnidarian has a behavioral reaction to light, but it remains unknown which of its many opsins functions in light detection. Here, we used phylogenetics and RNA-seq to investigate the molecular evolution of opsin genes and their expression in H. vulgaris. We explored where opsin genes are located relative to each other in an improved genome assembly and where they belong in a cnidarian opsin phylogenetic tree. In addition, we used RNA-seq data from different tissues of the H. vulgaris adult body and different time points during regeneration and budding stages to gain insight into their potential functions.ResultsWe identified 45 opsin genes in H. vulgaris, many of which were located near each other suggesting evolution by tandem duplications. Our phylogenetic tree of cnidarian opsin genes supported previous claims that they are evolving by lineage-specific duplications. We identified two H. vulgaris genes (HvOpA1 and HvOpB1) that fall outside of the two commonly determined Hydra groups; these genes possibly have a function in nematocytes and mucous gland cells respectively. We also found opsin genes that have similar expression patterns to phototransduction genes in H. vulgaris. We propose a H. vulgaris phototransduction cascade that has components of both ciliary and rhabdomeric cascades.ConclusionsThis extensive study provides an in-depth look at the molecular evolution and expression of H. vulgaris opsin genes. The expression data that we have quantified can be used as a springboard for additional studies looking into the specific function of opsin genes in this species. Our phylogeny and expression data are valuable to investigations of opsin gene evolution and cnidarian biology.

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Molecular Details of Retinal Guanylyl Cyclase 1/GCAP-2 Interaction

Cited by 11 publications

References 52 publications

Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A

Normal GCAPs partly compensate for altered cGMP signaling in retinal dystrophies associated with mutations in GUCA1A

A Simple Cross-Linking/Mass Spectrometry Workflow for Studying System-wide Protein Interactions

Molecular evolution and expression of opsin genes in Hydra vulgaris

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