Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A remarkable resemblance between the appearance of opacity in lysozyme--salt water mixtures and the development of opacity in cold cataract in the young rat lens is strong evidence that cold cataract is fundamentally a phase separation of the "protein-water binary mixture" in the lens.
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PMID:Phase separation of a protein-water mixture in cold cataract in the young rat lens. 88 36

25 patients admitted for cataract surgery were subjected to conjunctival bacterial culturings preoperatively and during the postoperative observation period. Simultaneously lactoferrin (LF), lysozyme (LY) and secretory immunoglobulin A (s-IgA) were measured in tears. The preoperative flora disclosed the growth of Staphylococcus albus (SA) and diphtheroids. Other species were only sporadically present. There was a significant rise in number of patients affected by SA and diphtheroids postoperatively (from 60 to 80%), whereas other bacteria were not present to any significant extent. LF, LY and s-IgA concentration decreased to about 50% of the preoperative level in the early postoperative period gradually returning towards their initial concentration. Correlating an antibacterial score with bacterial score we found a significant inverse relationship between the two (P less than 0.05).
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PMID:Bacterial growth in the conjunctival sac and the local defense of the outer eye. 300 13

Compounds capable of inhibiting protein aggregation may find pharmacological applications in the treatment of a number of diseases called protein condensation diseases [Benedek (1997)], which include cataract, biliary and urinary lithiasis and certain rheumatic diseases. We examined the effect of selected compounds on heat-induced aggregation human serum albumin (HSA), IgG and lysozyme. HSA (0.2% w/v in 0.066 M sodium phosphate pH 5.3 at 22 degrees C), IgG (0.5% w/v in 0.066 M Tris pH 8.0 at 22 degrees C), and L (0.2 % w/v in 0.066 M CAPS pH 11.0 at 22 degrees C) were heated for 30 min at 70 degrees C in the presence or absence of different concentrations of the substance under examination and heat-induced aggregation of 100 microl aliquots was evaluated by measuring the absorbance at 595 nm using an automatic microplate reader. In these conditions, inhibition of aggregation could be due to an anti-denaturant effect or to interferences with the aggregation of denatured molecules, as previously described [Saso, Casini et al. (1998)]. However, this distinction may not be pharmacologically relevant when the target of the therapy is the prevention of abnormal phenomena of protein aggregation. Inorganic salts like NaCl and CaCl2 were active on the three proteins (IgG > HSA > L) but many ligands of HSA such as tryptophan, N-acetyl-tryptophan, caprylic acid, capric acid, cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid and bendazac were active on their carrier but not on IgG and L, indicating that the latter proteins are more difficult to protect and that specific anti-denaturant and/or anti-aggregant compounds should be developed.
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PMID:Effect of selected substances on heat-induced aggregation of albumin, IgG and lysozyme. 992 Mar 43

Understanding aqueous protein-protein interactions is crucial for the development of a molecular-thermodynamic model for salt-induced protein precipitation. In addition, protein interactions are important in many disease states, including cataract formation and alpha-amyloid diseases. Fluorescence anisotropy provides a means to measure intermolecular interactions. In this work, monomer-dimer equilibrium of the peptide T4 LYS(11-36) was studied by fluorescence anisotropy over the pH range 4-7 and the NaCl concentration range 0.0-1.0 M, in a 25 mM sodium phosphate buffer. This 26 amino-acid peptide is derived from the beta-sheet region of the T4 lysozyme molecule and has the potential to form amyloid fibrils. The association constant for dimerization increases with rising pH and ionic strength. The potential of mean force for peptide-peptide interactions was calculated from these association constants. Circular-dichroism measurements show that the peptide becomes more structured as the pH rises, possibly contributing to increased association.
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PMID:Interactions of proteins in aqueous electrolyte solutions from fluorescence anisotropy and circular-dichroism measurements. 1079 32

The eye lenses of the Antarctic nototheniid fishes that inhabit the perennially freezing Antarctic seawater are transparent at -2 degrees C, whereas the cold-sensitive mammalian and tropical fish lenses display cold-induced cataract at 20 degrees C and 7 degrees C, respectively. No cold-cataract occurs in the giant Antarctic toothfish Dissostichus mawsoni lens when cooled to temperatures as low as -12 degrees C, indicating highly cold-stable lens proteins. To investigate this cold stability, we characterised the lens crystallin proteins of the Antarctic toothfish, in parallel with those of the sub-tropical bigeye tuna Thunnus obesus and the endothermic cow Bos taurus, representing three disparate thermal climes (-2 degrees C, 18 degrees C and 37 degrees C, respectively). Sizing chromatography resolved their lens crystallins into three groups, alpha/betaH, beta and gamma, with gamma crystallins being the most abundant (>40%) lens proteins in fish, in contrast to the cow lens where they comprise only 19%. The upper thermal stability of these crystallin components correlated with the body temperature of the species. In vitro chaperone assays showed that fish alpha crystallin can protect same-species gamma crystallins from heat denaturation, as well as lysozyme from DTT-induced unfolding, and therefore are small Heat Shock Proteins (sHSP) like their mammalian counterparts. Dynamic light scattering measured an increase in size of alphagamma crystallin mixtures upon heating, which supports formation of the alphagamma complex as an integral part of the chaperone process. Surprisingly, in cross-species chaperone assays, tuna alpha crystallins only partly protected toothfish gamma crystallins, while cow alpha crystallins completely failed to protect, indicating partial and no alphagamma interaction, respectively. Toothfish gamma was likely to be the component that failed to interact, as the supernatant from a cow alpha plus toothfish gamma incubation could chaperone cow gamma crystallins in a subsequent heat incubation, indicating the presence of uncomplexed cow alpha. This suggests that the inability of toothfish gamma crystallins to fully complex with tuna alpha, and not at all with the cow alpha crystallins, may have its basis in adaptive changes in the protein that relate to the extreme cold-stability of the toothfish lens.
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PMID:Cold-stable eye lens crystallins of the Antarctic nototheniid toothfish Dissostichus mawsoni Norman. 1557 59

We present a novel hypothesis for the molecular mechanism of autosomal dominant cataract linked to two mutations in the alphaA-crystallin gene of the ocular lens. AlphaA-crystallin is a molecular chaperone that plays a critical role in the suppression of protein aggregation and hence in the long term maintenance of lens optical properties. Using a steady state binding assay in which the chaperone-substrate complex is directly detected, we demonstrate that the mutations result in a substantial increase in the level of binding to non-native states of the model substrate T4 lysozyme. The structural basis of the enhanced binding is investigated through equivalent substitutions in the homologous heat shock protein 27. The mutations shift the oligomeric equilibrium toward a dissociated multimeric form previously shown to be the binding-competent state. In the context of a recent thermodynamic model of chaperone function that proposes the coupling of small heat shock protein activation to the substrate folding equilibrium (Shashidharamurthy, R., Koteiche, H. A., Dong, J., and McHaourab, H. S. (2005) J. Biol. Chem. 280, 5281-5289), the enhanced binding by the alphaA-crystallin mutants is predicted to shift the substrate folding equilibrium toward non-native intermediates, i.e. the mutants promote substrate unfolding. Given the high concentration of alphaA-crystallin in the lens, the molecular basis of pathogenesis implied by our results is a gain of function that leads to the binding of undamaged proteins and subsequent precipitation of the saturated alpha-crystallin complexes in the developing lens of affected individuals.
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PMID:Mechanism of a hereditary cataract phenotype. Mutations in alphaA-crystallin activate substrate binding. 1653 22

We have studied the effect of a crowded (macromolecular) solution on reaction rates of the decarboxylating enzymes urease, pyruvate decarboxylase and glutamate decarboxylase. A variety of crowding agents were used including haemoglobin, lysozyme, various dextrans and polyethylene glycol. Enzyme reaction rates of all three enzymes show two different types of effect that separate the globular proteins from the polysaccharides/polymers. Increasing concentration of globular proteins caused a dramatic rise in enzyme activity up to 30% crowding concentration then the activity decreased, whereas the polymers caused a concentration dependent decrease in activity. The viscosities of the globular proteins were low compared to the polymers. The increased activity with proteins may be due to the decreased amount of free water, which leads to higher effective concentration of substrates, or to an increased oligomeric state by self-association. The lower activities of all enzymes with all agents at high concentrations may be explained by a decrease in rates of diffusion. An increase in protein crowding (decrease in cell water content) may contribute to pathological conditions including cataract and Alzheimer's disease.
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PMID:The effect of the presence of globular proteins and elongated polymers on enzyme activity. 1672 Jan 13

We have identified sequence and structural determinants of oligomer size, symmetry, and polydispersity in the small heat shock protein super family. Using an insertion mutagenesis strategy that mimics evolutionary sequence divergence, we induced the ordered oligomer of Methanococcus jannaschii Hsp16.5 to transition to either expanded symmetric or polydisperse assemblies. A hybrid approach combining spin labeling EPR and cryoelectron microscopy imaging at 10A resolution reveals that the underlying plasticity is mediated by a packing interface with minimal contacts and a flexible C-terminal tether between dimers. Twenty-four dimeric building blocks related by octahedral symmetry assemble into the expanded symmetric oligomer. In contrast, the polydisperse variant has an ordered dimeric building block that heterogeneously packs to yield oligomers of various sizes. Increased exposure of the N-terminal region in the Hsp16.5 variants correlates with enhanced binding to destabilized mutants of T4 lysozyme, whereas deletion of this region reduces binding. Transition to larger intermediates with enhanced substrate binding capacity has been observed in other small heat shock proteins including lens alpha-crystallin mutants linked to congenital cataract. Together, these results provide a mechanistic perspective on substrate recognition and binding by the small heat shock protein superfamily.
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PMID:Cryoelectron microscopy and EPR analysis of engineered symmetric and polydisperse Hsp16.5 assemblies reveals determinants of polydispersity and substrate binding. 1707 34

Hereditary cataract is a phenotypically and genetically heterogeneous lens disease that is responsible for a significant proportion of the visual impairment and blindness that occurs in children. In a five-generation Chinese family with autosomal dominant inherited congenital cataract, clinical examination showed three cataract phenotypes: punctuate, nuclear, and total cataracts. Linkage analysis was performed and positive two-point LOD scores (with maximum of 4.43 and 4.27 at theta=0) were obtained for markers D21S1411 and D21S1890 on chromosome 21q22.3, flanking the CRYAA (alphaA-crystallin-encoding gene) locus. Sequencing of CRYAA revealed a novel heterozygous G>A transition (c.346G>A) in exon 3 that cosegregated with the disease phenotype and results in a conservative substitution of Arg to His at codon 116 (p.R116H). To understand the molecular basis of cataract formation, mutant and wild-type alphaA-crystallins were expressed in E. coli. RP-HPLC (reverse phase-high-performance liquid chromatography) suggested an increased hydrophobicity of the mutant recombinant protein, compared to that of wild-type alphaA-crystallins. Furthermore, loss of chaperone activity of the mutant was seen in DTT (DL-dithiothreitol)-induced insulin aggregation assay. FPLC (fast protein liquid chromatography) purification showed that the His-116 mutant protein had increased binding affinity to lysozyme. Gain of activated lysozyme binding, elevation of hydrophobicity and loss of chaperone activity of the mutant protein may be some of the molecular mechanisms underlying cataract in this large family.
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PMID:A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family. 1840 50

We report the quantitative, label-free analysis of protein-protein interactions in free solution within picoliter volumes using backscatter interferometry (BSI). Changes in the refractive index are measured for solutions introduced on a PDMS microchip allowing determination of forward and reverse rate constants for two-mode binding. Time-dependent BSI traces are directly fit using a global analysis approach to characterize the interaction of the small heat-shock protein alpha-Crystallin with two substrates: destabilized mutants of T4 lysozyme and the in vivo target betaB1-Crystallin. The results recapitulate the selectivity of alphaB-Crystallin differentially binding T4L mutants according to their free energies of unfolding. Furthermore, we demonstrate that an alphaA-Crystallin mutant linked to hereditary cataract has activated binding to betaB1-Crystallin. Binding isotherms obtained from steady-state values of the BSI signal yielded meaningful dissociation constants and establishes BSI as a novel tool for the rapid identification of molecular partners using exceedingly small sample quantities under physiological conditions. This work demonstrates that BSI can be extended to screen libraries of disease-related mutants to quantify changes in affinity and/or kinetics of binding.
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PMID:Free-solution label-free detection of alpha-crystallin chaperone interactions by back-scattering interferometry. 1917 88


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