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Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding.
Vishnivetskiy SA, Ostermaier MK, Singhal A, Panneels V, Homan KT, Glukhova A, Sligar SG, Tesmer JJ, Schertler GF, Standfuss J, Gurevich VV
(2013) Cell Signal 25: 2155-62
MeSH Terms: Animals, Arrestin, Cattle, Cholesterol, HDL, G-Protein-Coupled Receptor Kinase 1, Gene Expression Regulation, Isoenzymes, Mutation, Night Blindness, Opsins, Phosphoproteins, Phosphorylation, Protein Binding, Protein Isoforms, Protein Multimerization, Retinal Rod Photoreceptor Cells, Rhodopsin, Signal Transduction
Show Abstract · Added December 10, 2013
The effects of activating mutations associated with night blindness on the stoichiometry of rhodopsin interactions with G protein-coupled receptor kinase 1 (GRK1) and arrestin-1 have not been reported. Here we show that the monomeric form of WT rhodopsin and its constitutively active mutants M257Y, G90D, and T94I, reconstituted into HDL particles are effectively phosphorylated by GRK1, as well as two more ubiquitously expressed subtypes, GRK2 and GRK5. All versions of arrestin-1 tested (WT, pre-activated, and constitutively monomeric mutants) bind to monomeric rhodopsin and show the same selectivity for different functional forms of rhodopsin as in native disc membranes. Rhodopsin phosphorylation by GRK1 and GRK2 promotes arrestin-1 binding to a comparable extent, whereas similar phosphorylation by GRK5 is less effective, suggesting that not all phosphorylation sites on rhodopsin are equivalent in promoting arrestin-1 binding. The binding of WT arrestin-1 to phospho-opsin is comparable to the binding to its preferred target, P-Rh*, suggesting that in photoreceptors arrestin-1 only dissociates after opsin regeneration with 11-cis-retinal, which converts phospho-opsin into inactive phospho-rhodopsin that has lower affinity for arrestin-1. Reduced binding of arrestin-1 to the phospho-opsin form of G90D mutant likely contributes to night blindness caused by this mutation in humans.
© 2013.
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18 MeSH Terms
Insights into congenital stationary night blindness based on the structure of G90D rhodopsin.
Singhal A, Ostermaier MK, Vishnivetskiy SA, Panneels V, Homan KT, Tesmer JJ, Veprintsev D, Deupi X, Gurevich VV, Schertler GF, Standfuss J
(2013) EMBO Rep 14: 520-6
MeSH Terms: Arrestin, Crystallography, X-Ray, Eye Diseases, Hereditary, Genetic Diseases, X-Linked, HEK293 Cells, Humans, Models, Molecular, Mutation, Missense, Myopia, Night Blindness, Protein Binding, Protein Stability, Protein Structure, Secondary, Protein Structure, Tertiary, Rhodopsin, Schiff Bases, Structural Homology, Protein, Transition Temperature
Show Abstract · Added February 12, 2015
We present active-state structures of the G protein-coupled receptor (GPCRs) rhodopsin carrying the disease-causing mutation G90D. Mutations of G90 cause either retinitis pigmentosa (RP) or congenital stationary night blindness (CSNB), a milder, non-progressive form of RP. Our analysis shows that the CSNB-causing G90D mutation introduces a salt bridge with K296. The mutant thus interferes with the E113Q-K296 activation switch and the covalent binding of the inverse agonist 11-cis-retinal, two interactions that are crucial for the deactivation of rhodopsin. Other mutations, including G90V causing RP, cannot promote similar interactions. We discuss our findings in context of a model in which CSNB is caused by constitutive activation of the visual signalling cascade.
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Juvenile neuronal ceroid lipofuscinosis (Batten disease) CLN3 mutation (Chrom 16p11.2) with different phenotypes in a sibling pair and low intensity in vivo autofluorescence.
Mantel I, Brantley MA, Bellmann C, Robson AG, Holder GE, Taylor A, Anderson G, Moore AT
(2004) Klin Monbl Augenheilkd 221: 427-30
MeSH Terms: Blindness, Child, Chromosome Deletion, Chromosomes, Human, Pair 16, Corneal Dystrophies, Hereditary, DNA Mutational Analysis, Disease Progression, Electroretinography, Female, Fluorescein Angiography, Homozygote, Humans, Male, Membrane Glycoproteins, Molecular Chaperones, Neuronal Ceroid-Lipofuscinoses, Night Blindness, Phenotype, Retinal Degeneration
Show Abstract · Added December 10, 2013
BACKGROUND - The neuronal ceroid lipofuscinoses (Batten disease) are a heterogeneous group of autosomal recessively inherited disorders causing progressive neurological failure, mental deterioration, seizures and visual loss secondary to retinal dystrophy. The juvenile type is of special interest to the ophthalmologist as visual loss is the earliest symptom of the disorder.
HISTORY AND SIGNS - We present two siblings with severe retinal dystrophy due to juvenile Batten disease. Sibling A (age 10) presented with visual loss, photophobia and night blindness, starting at age 4. His vision was perception of light by the age of 10.5 years. Fundus examination revealed severe pigmentary retinopathy. Sibling B (age 7) presented with night vision difficulties. Fundus examination revealed a bull's eye maculopathy with minimal peripheral atrophic changes. In vivo autofluorescence level was found to be very low. Electroretinography (ERG) showed generalized retinal dysfunction involving both cone and rod systems, with an electronegative maximal response. In both siblings vacuolated lymphocytes were found on a peripheral blood film and on molecular genetic testing both were homozygous for the commonly reported 1.02-kb deletion of the CLN3 gene.
THERAPY AND OUTCOME - Although there is no effective treatment, the early diagnosis allowed accurate genetic and social counseling.
CONCLUSIONS - Juvenile Batten disease should be considered in children with a retinal dystrophy, especially where there is a bull's eye maculopathy and an abnormal full field ERG. The novel finding of very low in vivo autofluorescence is consistent with histopathological studies and may be secondary to photoreceptor cell loss.
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19 MeSH Terms