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using cryo-electron microscopy, it is shown that the major interactions between activated rhodopsin and Gi are mediated by the C-terminal helix of the Gi alpha-subunit, which is wedged into the cytoplasmic cavity of the transmembrane helix bundle and directly contacts the amino terminus of helix 8 of rhodopsin
The identification of the pathogenic variant p.E113 K is the first description of a naturally-occurring mutation in the Schiff base counterion of RHO in patients. The heterozygous mutation c.337G > A in exon 1 was confirmed in the retinitis pigmentosa index patient as well as in five stationary night blindness-affected relatives.
data provide the first evidence that T17M rhodopsin mutant disrupts C3 secretion via the induction of ROS and the suppression of TWIST1.
Wild-type opsin mainly formed oligomers. Only a minor population formed aggregates. The G188R opsin mutant mainly formed aggregates. When wild-type opsin and G188R opsin were coexpressed in cells, properly folded wild-type opsin did not aggregate with G188R opsin and was trafficked normally to the cell membrane. The autosomal dominant phenotype due to misfolded opsin mutants is not due to WT-mutant physical interaction.
Data suggest that retinitis pigmentosa-associated mutation G51A behaves differently in human rhodopsin compared to bovine rhodopsin; human rhodopsin is more thermally stable than ancestral ancestrally reconstructed mammalian rhodopsin.
These findings provide a new understanding of the effects of oxLDL on endothelial proliferation, which is essential for developing new treatments against neovascularization and progression of atherosclerosis.
The metformin-rescued P23H rhodopsin was still intrinsically unstable and led to increased structural instability of the rod outer segments. These data suggest that improving the traffic of misfolding rhodopsin mutants is unlikely to be a practical therapy, but also highlights the potential of altering translation through AMPK to improve protein function in other protein misfolding diseases
Study reports an X-ray free electron laser crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular beta sheet with the N-terminal beta strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338.
results suggest that nonsense-mediated mRNA decay modulates the severity of retinitis pigmentosa in patients with nonsense mutations in the rhodopsin gene
both the charged G90D(2.57) and the hydrophobic T94I(2.61) mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E113(3.28) We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients.
A mutation-independent strategy appears viable in this specific context but certain mutations could significantly influence ribozyme or RNAi efficacy through impact on accessibility at the target annealing site/region.
a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene cosegregated with all retinitis pigmentosa affected individuals in the family.
Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7.
Functional role of positively selected amino acid substitutions in mammalian rhodopsin evolution has been uncovered for a large number of mammalian species.
Our study shows that RHO mutations are a major cause of adRP in this cohort and are responsible for 28% of adRP families.
analysis of the crystal structure of the rhodopsin-arrestin complex
A whole-exome sequencing approach led to identification of a deletion in RHO through detection of a new linked variant in COL6A6 in autosomal dominant retinitis pigmentosa.
These insights into the dynamics of the ground states and the early photocycle stages enhance our understanding of the channel function of Channel rhodopsin.
Studies indicate that misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis.
FIP3 (RAB11-FIP3) promotes the activity of Rab11a and the ASAP1 in the Arf4-dependent ciliary transport of the sensory receptor rhodopsin.
The efficiency of CRISPR/Cas9 for gene targeting, coupled with the large number of mutations associated with retinitis pigmentosa, provided a backdrop for the rapid isolation of novel alleles in zebrafish that phenocopy disease.
overexpression of full-length rhodopsin or its cytoplasmic tail domain, but not of rhodopsin lacking the cytoplasmic tail, exacerbated rod degeneration in kif3a mutants, implying an important role of the cytoplasmic tail in rod degeneration.
expression as well as the protein localization of rhodopsin in the zebrafish from larval to adult stage were demonstrated; results demonstrated the involvement of rhodopsin in the zebrafish pineal gland physiology particularly in light capture during the zebrafish lifespan
Mitogen-associated protein kinase and protein kinase A regulate rhodopsin transcription through parallel signal transduction pathways
Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription.
we show that OPN2 and OPN4 participate in immediate pigment darkening induced by UVA in murine normal and malignant melanocytes through a conserved common pathway
Photoactivation of rhodopsin increases near-Infrared backscattering from rods and causes lengthening of their rod outer segment.
Specific visible radiation facilitates lipolysis in mature 3T3-L1 adipocytes via rhodopsin-dependent beta3-adrenergic signaling.
By modifying culture conditions in the SFEBq protocol, we obtained rod-dominated 3D retinas and S- and M-opsin expressing 3D retinas.
Rab8a and Rab11a Are Dispensable for Rhodopsin Transport in Mouse Photoreceptors
This study demonstrated that Rhodopsin Phosphorylation on Dark Adaptation in Mouse Rods.
Findings indicate that Rho and ROCK knockout may improve the behavior of mice and prevent MPTP-induced dopaminergic neurons damage by regulating Sema3A, PlexinA and NRP-1 in a mouse model of Parkinson's disease.
The authors elucidated this dependency by showing that guanylate cyclase-1 is a novel rhodopsin-binding protein.
Eliminating Cngb1 and reducing RDS leads to additive defects in RDS expression levels and rod electroretinogram (ERG) function, (e.g., Cngb1-/-/rds+/- versus rds+/- or Cngb1-/-) but not to additive defects in rod ultrastructure.
These findings reveal that an early and significant pathophysiologic effect of endoplasmic reticulum stress in photoreceptors is the highly efficient elimination of misfolded rhodopsin protein.
Data show that G90D1 ribozyme efficiently and specifically cleaved the mutant transcript of the G90D mutation in the rhodopsin gene while G90D2 ribozyme cleaved both WT and mutant transcript.
These results provide precise genotypic information of the P23H-1 rat with additional phenotypic characterization that will serve basis for therapeutic interventions, especially for those aiming at gene editing.
Data show that misfolded opsin mutants form aggregates in the endoplasmic reticulum.
Data show that the step-like responses of serine-only rhodopsin reflect slow and stochastic arrestin binding.
Data indicate that genomic sequences from the rhodopsin gene can improve the efficacy of rhodopsin gene therapy in the rhodopsin knockout (RKO) mouse model of retinitis pigmentosa (RP).
Peripherin-2 links CNGB1 to the light-detector rhodopsin in outer segments of rod photoreceptors.
p27(kip1) promotes mesenchymal migration and hinders amoeboid migration upstream of the Rho/ROCK pathway.
Data indicate that the number of nanodomains present in a single disc was dependent on the number of rhodopsin molecules incorporated into the membrane.
We examine and compare the contribution of endoplasmic reticulum stress to retinal degeneration in several vertebrate models of retinitis pigmentosa generated through expression of mutant rhodopsins.
Retinal degeneration in the P23H (proline-to-histidine) rhodopsin mutation is partially reversed, with regeneration of rod photoreceptors recovering normal morphology in a retinitis pigmentosa model.
the Xenopus rhodopsin gene has conserved transcriptional activators
These results support a role for rhoP23H misfolding and inner segment accumulation in rod death.
The newly identified ciliary targeting VxPx motif present in rhodopsin binds the small GTPase Arf4 and regulates its association with the trans-Golgi network.
the rhodopsin is densely packed in the retina and the rhodopsin molecules are not aligned well.
Phototransduction, even when initiated by wild type rhodopsin, is altered in a way progressive with level of retinal degeneration. A model introduces idea of binding site for carboxy terminus of rhodopsin on rhodopsin kinase.
Data indicate molecular dynamics simulations and site-directed fluorescence experiments on arrestin-1 interactions with rhodopsin, showing that loops within the C-edge of arrestin function as a membrane anchor.
the photoreceptor pathology associated with expression of these enigmatic Retinitis pigmentosa-associated rhodopsin pigments arises from their unexpected inability to dimerize via transmembrane helices 1 and 5
Rhodopsin mutant E113Q could have the potential for use as a template of anion biosensors at visible wavelength.
The study shows that, compared to the inactive 11-cis-retinal case, trans-retinal rhodopsin is able to undergo protonated Schiff base (PSB) deprotonation due to a change in the conformation of the retinal and a consequent alteration in the hydrogen-bond (HB) network in which PSB and the counterion Glu113 are embedded.
These findings revealed a total water flux between the bulk and the protein inside in the Meta II state, and suggested that these pathways provide water molecules to the crucial sites of the activated rhodopsin.
Data suggest that a hetero-multimer complex forms between light-activated rhodopsin and light-activated heterotrimeric transducin (T-alpha-1, Gnb1, Gngt1); the stoichiometry is 1:1 rhodopsin:transducin. The complex appears to form on native rod outer segment membranes upon light activation.
Study presents a comprehensive analysis of the kinetics and thermodynamics of the recombination reaction between opsin and 11-cis-retinal (11CR) to form the mature visual pigment, Rho; and found that the lipid bilayer environment is important for ligand binding in Rho.
In response to light-induced isomerization of the retinal chromophore rhodopsin, hydrogen-bonding interactions involving these C=O groups are released, thus facilitating repacking of H5 and H7 onto the transmembrane core of the receptor.
rhodopsin can tolerate a second Lys in the retinal binding pocket and suggest that an evolutionary intermediate with two Lys could allow migration of the Schiff base Lys to a position other than the observed, highly conserved location in the seventh TM helix
multiconfigurational quantum chemistry is used to compare the isomerization mechanisms of the sensory rhodopsin from the cyanobacterium Anabaena PCC 7120 (ASR) and of the bovine rhodopsin (Rh).
show that although the basic activation pathways of human and bovine rhodopsin are similar, structural deviations exist in the inactive conformation and during receptor activation, even between closely related rhodopsins
Data suggest that, upon activation/deactivation of RHO, the main conformational changes found in molecular dynamic simulations are distributed throughout transmembrane bundle rather than localized to specific sites (i.e., conserved sequences).
DMPC/DHPC bicelles dramatically increase the thermal stability of the rhodopsin mutants G90V and N55K.
The molecular mechanism of the ultrafast reversible photoreaction of visual pigment rhodopsin may be used as a concept for the development of an ultrafast optical molecular switch.
Formation and decay of the arrestin.rhodopsin complex in native disc membranes.
Phospholipid scrambling is a constitutive activity of rhodopsin, distinct from its light-sensing function.
maps of information flow were calculated in A2 A adenosine receptor (A2 A AR) and bovine rhodopsin and identified key residues for signal transductions and their pathways.
One site on rhodopsin can interact with multiple structurally separate sites on arrestin that are almost 30 angstroms apart.
A comparison of melanopsin with the mechanisms documented for vertebrate (bovine) and invertebrate (squid) visual photoreceptors shows that such a mechanism is not affected by the diversity of the three chromophore cavities.
The form-deprived experimental myopia groups showed an increased expression of rhodopsin and its mRNA compared to the controls.
Retinitis pigmentosa is an inherited progressive disease which is a major cause of blindness in western communities. It can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disorder. In the autosomal dominant form,which comprises about 25% of total cases, approximately 30% of families have mutations in the gene encoding the rod photoreceptor-specific protein rhodopsin. This is the transmembrane protein which, when photoexcited, initiates the visual transduction cascade. Defects in this gene are also one of the causes of congenital stationary night blindness.
opsin 2, rod pigment
, Rhodopsin (retinitis pigmentosa 4, autosomal dominant)
, retinal rod opsin pigment rh1.1
, rod opsin
, L opsin
, LWS opsin
, Long Wavelength Sensitive opsin
, Red Opsin
, Rod Opsin
, opsin 2
, rhodopsin (opsin 2, rod pigment) (retinitis pigmentosa 4, autosomal dominant)