Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous retinopathies, some of which have been shown to result from mutations in two different known retinal genes, rhodopsin (3q) and peripherin-rds (6p). Three additional anonymous loci at 7p, 7q and pericentric 8 have been implicated by linkage studies. There are still, however, a few families in which all known loci have been excluded. In this report we present data indicating a location, on the short arm of chromosome 17, for the autosomal dominant RP (ADRP) locus in a large South African (SA) family of British ancestry. Positive two-point lod scores have been obtained for nine markers (D17S938, Z = 5.43; D17S796, Z = 4.82; D17S849, Z = 3.6; D17S786, Z = 3.55; TP53, Z = 3.55; D17S578, Z = 3.29; D17S960, Z = 3.16; D17S926, Z = 1.51; D17S804, Z = 0.47 all at theta = 0.10 except D17S804 and D17S926, theta = 0.20). These data provide definitive evidence for the localization of an ADRP gene on chromosome 17p. The human recoverin gene has been localized to 17p13.1 and was consequently a prime candidate for ADRP in the family studied. However, mutation screening of the three exons of this gene failed to produce any evidence of recoverin being the gene involved in the pathogenesis of ADRP in this SA family.
Hum Mol Genet 1994 Jun
PMID:A new locus for autosomal dominant retinitis pigmentosa on the short arm of chromosome 17. 795 Dec 36

In this paper an algorithm which locates helical transmembrane segments is described. It is shown that given the location of transmembrane helices of a protein, corresponding helices in another membrane related protein can be pinpointed. The method seems to be extremely insensitive to sequence identity but highly sensitive to the property of a sequence to assume transmembrane helical structure. As an example, using the present method, a sequence alignment between bacteriorhodopsin and human rhodopsin is carried out and it provides a good starting point for homology modeling of this G-protein coupled receptor. It is difficult to obtain this particular alignment using the traditional methods because of poor sequence homology. There are indications that hint at the broader range of applicability of the presented method.
J Mol Biol 1994 Oct 28
PMID:New alignment strategy for transmembrane proteins. 796 67

C5a is a 74 amino acid peptide cleaved from the fifth component of the complement system after activation of either the alternative or classical pathways. It is a potent chemoattractant for neutrophils and monocytes binding to identical receptors on the cell surface. Following the cloning of the cDNA encoding for the human complement C5a receptor, revealing it to be a member of the rhodopsin superfamily of G-protein coupled receptors, a model for the interaction of the C5a receptor with its ligand was proposed, the structure for the receptor being modelled on that of the well defined receptor bacteriorhodopsin. In this model two key residues of the receptor, aspartate82 and either glutamate179 or glutamate 180 were proposed to make up part of the binding site for C5a, acting as counter ions for arginine74 and arginine40, respectively of the C5a molecule. Replacement of aspartate82, glutamate179 and glutamate180 of the C5a receptor with asparagine and glutamine, respectively was shown to have little effect on the dissociation constant of the receptor as detected by Scatchard analysis and competitive binding assays. Hence this modus operandi for the interaction of C5a with its receptor can be rejected.
Mol Immunol 1994 Jul
PMID:Site directed mutagenesis of the complement C5a receptor--examination of a model for its interaction with the ligand C5a. 803 35

Recently, inositol hexakisphosphate (phytic acid) was shown to bind to photoreceptor arrestin and block its interaction with rhodopsin. Such an interaction might predict that inositol polyphosphates could alter G protein-coupled receptor desensitization. To investigate the possible roles of higher inositol polyphosphates on receptor desensitization, we have expressed the rat substance P receptor in Xenopus laevis oocytes. The functional expression of substance P receptor was monitored by voltage-clamp recording of substance P-induced Ca(2+)-dependent Cl- currents. When control oocytes were stimulated with substance P (30 nM), after 10 min of washing the second responses to substance P were approximately 15% of the first responses. Cytosolic injection of inositol pentakisphosphate (100 microM) or inositol hexakisphosphate (100 microM) inhibited the reduction of the second substance P-induced current responses, maintaining the second responses to 57-58% of the initial responses. The protective effects of inositol pentakisphosphate and inositol hexakisphosphate against agonist-induced desensitization were concentration and time dependent and structurally specific, in that inositol hexasulfate and inositol tris- and tetrakisphosphate isomers were inactive. Microinjection of inositol hexakisphosphate did not (a) change the potency of substance P or the sensitivity of the expressed substance P receptor to substance P, (b) inhibit 12-O-tetradecanoylphorbol-13-acetate-induced loss of substance P-induced current responses, or (c) alter the currents elicited by microinjection of inositol-1,4,5-trisphosphate. These results suggest that inositol pentakisphosphate and inositol hexakisphosphate have specific inhibitory effects on the agonist-induced loss of responsiveness of the rat substance P receptor. Moreover, these protective effects of inositol hexakisphosphate against desensitization were also observed with the endogenous lysophosphatidic acid/phosphatidic acid receptor, indicating that this mechanism is not specific to ectopic receptors. These results suggest that inositol pentakisphosphate and inositol hexakisphosphate may be novel pharmacological tools for the study of agonist-induced desensitization.
Mol Pharmacol 1994 Aug
PMID:Attenuation of agonist-induced desensitization of the rat substance P receptor by microinjection of inositol pentakis-and hexakisphosphates in Xenopus laevis oocytes. 807

The amino acids that comprise the ligand binding sites of adenosine receptors have not been identified. Adenosine and its agonist analogues differ from ligands for the well studied biogenic amine receptors and rhodopsin in that the adenosine receptor agonists are larger, contain a ribose moiety, and are uncharged at physiological pH. Thus, the locations of the ligand binding pockets of the adenosine receptors could differ significantly from those of the biogenic amine receptors. This report describes the characterization of a purification-amenable truncated mutant of the canine A2a adenosine receptor and demonstrates that neither the long carboxyl-terminal tail nor the glycosidic moiety appears to be required for ligand binding. The dog thyroid A2a adenosine receptor cDNA (RDC8) was subcloned into the mammalian expression vector pCMV4. A mutant A2a construct, in which six histidines replaced residues 310-412 as the carboxyl terminus of the protein, also was prepared. When overexpressed transiently in COS M6 cells, the wild-type and mutant A2a receptors exhibited similar 2-[p-(2-[3H]carboxyethyl)phenylethylamino]-5'-N- ethylcarboxamidoadenosine saturation binding and competition curve profiles. The following biochemical techniques confirmed that the COS M6 cells were transcribing and translating A2a receptors of the expected molecular masses: (a) immunoblotting with an antipeptide antibody directed against the putative carboxyl-terminal side of the second extracellular loop (Tyr155-Val172) of the canine A2a adenosine receptor, (b) photoaffinity labeling with the A2a-selective agonist 125I-2-[4-[2-[2-[(4-azidophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl]phenyl]ethylamino-5'-N-ethylcarboxamidoad enosine (125I-azido-PAPA-APEC), and (c) partial purification of the hexahistidine-tagged receptor on Ni2+.nitrilotriacetic acid resin. A presumed A2a receptor (44 kDa) from rabbit striatal membranes also was detected with the antisera against amino acids Tyr155-Val172 of the RDC8 receptor. Not only could the mutant A2a receptor be photolabeled specifically with 125I-azido-PAPA-APEC but so too could unglycosylated A2a receptors (i.e., from tunicamycin-treated COS M6 cells), either full length or truncated. In all of these cases, photolabeling was attenuated by both agonist and antagonist competitors.
Mol Pharmacol 1994 May
PMID:A carboxyl-terminally truncated mutant and nonglycosylated A2a adenosine receptors retain ligand binding. 819 Jan 3

The regeneration of visual pigment in rod photoreceptors of the vertebrate retina requires an exchange of retinoids between the neural retina and the retina pigment epithelium (RPE). It has been hypothesized that interphotoreceptor retinoid-binding protein (IRBP) functions as a two-way carrier of retinoid through the aqueous compartment (interphotoreceptor matrix) that separates the RPE and the photoreceptors. The first part of this review summarizes the cellular and molecular biology of IRBP. Work on the IRBP gene indicates that the protein contains a four-fold repeat structure that may be involved in binding multiple retinoid and fatty acid ligands. These repeats and other aspects of the gene structure indicate that the gene has had an active and complex evolutionary history. IRBP mRNA is detected only in retinal photoreceptors and in the pineal gland; expression is thus restricted to the two photosensitive tissues of vertebrate organisms. In the second part of this review, we consider the results obtained in experiments that have examined the activity of IRBP in the process of visual pigment regeneration. We also consider the results obtained on the bleaching and regeneration of rhodopsin in the acutely detached retina, as well as in experiments testing the ability of IRBP to protect its retinoid ligand from isomerization and oxidation. Taken together, the findings provide evidence that, in vivo, IRBP facilitates both the delivery of all-trans retinol to the RPE and the transfer of 11-cis retinal from the RPE to bleached rod photoreceptors, and thereby directly supports the regeneration of rhodopsin in the visual cycle.
Mol Neurobiol 1993
PMID:Interphotoreceptor retinoid-binding protein (IRBP). Molecular biology and physiological role in the visual cycle of rhodopsin. 831 67

Retinitis Pigmentosa (RP) is the most prevalent degenerative retinal disease of mendelian origin, currently affecting approximately 1.5 million people worldwide. To date it has been established that a minimum of five different genes maybe involved in the pathogenesis of autosomal dominant forms of RP (adRP). The genes encoding two retinal specific proteins, rhodopsin and peripherin/RDS, have been implicated in causing adRP due to the observation of many different mutations in these genes in patients suffering from RP. The three remaining adRP genes have been mapped to specific regions of human chromosomes but as yet are uncharacterized. We have investigated if there is evidence for the presence of another locus in the genome which when mutated causes adRP. We have utilised polymorphic genetic markers which have previously been mapped to each of the regions known to harbour adRP genes, to test for the exclusion or linkage of the disease gene segregating in a pedigree of Irish origin and find no evidence for linkage. Hence we provide definitive evidence for the involvement of yet another locus. The implications of high levels of genetic heterogeneity inherent in adRP are discussed in relation to diagnosis, prognosis and future therapies.
Hum Mol Genet 1993 Jul
PMID:Exclusion of the involvement of all known retinitis pigmentosa loci in the disease present in a family of Irish origin provides evidence for a sixth autosomal dominant locus (RP8). 836 69

We examine in this paper one of the expected consequences of the hypothesis that modern proteins evolved from random heteropeptide sequences. Specifically, we investigate the lengthwise distributions of amino acids in a set of 1,789 protein sequences with little sequence identify using the run test statistic (ro) of Mood (1940, Ann. Math. Stat. 11, 367-392). The probability density of ro for a collection of random sequences has mean = 0 and variance = 1 [the N(0,1) distribution] and can be used to measure the tendency of amino acids of a given type to cluster together in a sequence relative to that of a random sequence. We implement the run test using binary representations of protein sequences in which the amino acids of interest are assigned a value of 1 and all others a value of 0. We consider individual amino acids and sets of various combinations of them based upon hydrophobicity (4 sets), charge (3 sets), volume (4 sets), and secondary structure propensity (3 sets). We find that any sequence chosen randomly has a 90% or greater chance of having a lengthwise distribution of amino acids that is indistinguishable from the random expectation regardless of amino acid type. We regard this as strong support for the random-origin hypothesis. However, we do observe significant deviations from the random expectation as might be expected after billions years of evolution. Two important global trends are found: (1) Amino acids with a strong alpha-helix propensity show a strong tendency to cluster whereas those with beta-sheet or reverse-turn propensity do not. (2) Clustered rather than evenly distributed patterns tend to be preferred by the individual amino acids and this is particularly so for methionine. Finally, we consider the problem of reconciling the random nature of protein sequences with structurally meaningful periodic "patterns" that can be detected by sliding-window, autocorrelation, and Fourier analyses. Two examples, rhodopsin and bacteriorhodopsin, show that such patterns are a natural feature of random sequences.
J Mol Evol 1993 Jan
PMID:The evolution of proteins from random amino acid sequences. I. Evidence from the lengthwise distribution of amino acids in modern protein sequences. 843 79

The efficacy of 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPOL), a metal independent superoxide dismutase (SOD) mimic, in ameliorating light-induced retinal degeneration was investigated. Thirty-six Lewis albino rats were exposed to green fluorescent light (490-580 nm, 160-180 foot-candles) for 24 hr, after dark adaptation for 24 hr. The animals received six intraperitoneal (IP) injections of TEMPOL (100 mg/kg) or an equivalent volume of saline solution (vehicle-treated control groups) at 6 hr intervals starting 6 hr before the light exposure and ending 24 hr after light exposure. Another six rats were used as unexposed controls. The animals were killed at 6 hr, 6 days and 14 days after light exposure. Retinal damage was assessed by light and electron microscopy, measurements of outer nuclear layer (ONL) thickness and rhodopsin levels and counting of macrophages in the subretinal space. After light exposure, the TEMPOL-treated rats showed mild edema of the retinal pigment epithelium (RPE), less densified inner segments (IS) at 6 hr and better preserved photoreceptors at 6 days and 14 days compared with vehicle-treated control groups. Morphometrically the ONL was thicker in the TEMPOL-treated rats than in the vehicle-treated control at 6 days (p<0.01) and 14 days (p<0.05) but no significant difference occurred at 6 hr (p>0.05). Rhodopsin levels in the TEMPOL-treated rats were significantly higher at 6 days (p<0.05) but not at 6 hr (p>0.05) or 14 days (p>0.05). Our results demonstrated that TEMPOL ameliorated light-induced retinal degeneration in rats. These findings are consistent with the hypothesis that superoxide radicals may play a crucial role in mediating light-induced retinal degeneration.
Res Commun Mol Pathol Pharmacol 1995 Sep
PMID:TEMPOL, a superoxide dismutase mimic, ameliorates light-induced retinal degeneration. 868 Jul 98

Photobiological processes are relevant for microorganisms for energy generation, protection against excess and/or damaging radiation, and for signalling. In this review we give an overview of the knowledge on the functioning of photosensors in microorganisms, with special emphasis on the conformational changes that lead to signal generation and transduction. Light is absorbed by specific chromophores, which are tuned, by their proteinaceous environment, to function optimally. These chromophores belong to three classes: tetrapyrroles, polyenes and aromatics. The chemical structure of photosensing pigment/protein complexes has been resolved for many of the photobiological processes that have a characteristic sensitivity in the visible and infrared part of the spectrum of (solar) radiation. However, knowledge about the structure of photoreceptors responsible for several physiologically well-characterized photoresponses to UV- and blue light is still lacking. For a limited number of phototransduction processes, the details of light-induced signal transfer are beginning to be understood in atomic detail. This applies particularly to two photosensors involved in phototactic responses in bacteria: sensory rhodopsin I (SR-I) from Halobacterium salinarium and photoactive yellow protein (PYP) from Ectothiorhodospira halophila. The SR-1 system is of special interest because the transducer accepting the signal from SR-1 was recently identified as Htr-1, a homologue of the methyl-accepting chemotaxis proteins which have been characterized in Escherichia coli. PYP, on the other hand, may be the first photosensor to actually reveal all relevant details of the kinetics, thermodynamics, and molecular motion of light-induced signal generation, through an understanding of how the photo-isomerization of the chromophore forces the sensor protein into the signalling state. Here we compare these photosensors and discuss common themes in the initiation of photosensory signal transduction in microorganisms in terms of the molecular properties of photosensors and their signalling state.
Mol Microbiol 1996 Aug
PMID:Photobiology of microorganisms: how photosensors catch a photon to initialize signalling. 887 32


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