Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.17 (lysozyme)
 21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Senile plaques and cerebrovascular amyloidosis are major histopathological lesions in the brains of aged dogs. Different types of amyloid beta protein (A beta) positive plaques are known: diffuse ones and neuritic plaques. Diffuse plaques may contain membrane-bound A beta and/or small amounts of amyloid fibrils. Neuritic plaques are cored plaques with clusters of amyloid fibrils and degenerating neurities. In human amyloid plaques, a pathogenetic role for microglia cells has been described. The aim of this investigation was to study microglia cells in relationship to canine plaques and to investigate the localisation of amyloid plaques in relationship to vasculature. The lesions were studied by hematoxylin and eosin Congo red staining and immunohistochemistry with anti-A beta for plaques, with Mac 387, anti lysozyme and a series of lectins for mononuclear cells, with anti von Willebrand Factor and Lycopersicon esculentum (tomato) lectin for the endothelium of brain capillaries. Diffuse A beta-positive plaques were found in dogs of 10.8 years and older, and cored A beta-positive plaques with birefringent amyloid in Congo red-stained sections in subjects of 15 years and older. Accumulation of microglia cells in relationship to the plaques was not obvious. With anti A beta 8-17 the distribution of the plaques in the cortical layers varied. The younger dogs had primarily diffuse plaques in the deeper layers of the cortical grey matter. The older dogs showed more cored plaques than diffuse plaques which were found throughout all cortical grey matter layers. With anti A beta x-42 more plaques were found positive, especially diffuse ones, whereas staining results of anti A beta x-40 were more confined to amyloid plaques and vascular amyloid. A close spatial relationship was found between the cored plaques and capillaries.
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PMID:Canine counterpart of senile dementia of the Alzheimer type: amyloid plaques near capillaries but lack of spatial relationship with activated microglia and macrophages. 1296 16

Formation of amyloid deposits from the Ile56Thr or Asp67His variants of human lysozyme is a hallmark of autosomal hereditary systemic amyloidosis. It has recently been shown that amyloid fibrils can be formed in vitro from wild-type (WT), I56T, or D67H lysozyme variants upon prolonged incubation at acidic pH and elevated temperatures (1). Here, we have used hydrostatic pressure as a tool to generate amyloidogenic states of WT and variant lysozymes at physiological pH. WT or variant lysozyme samples were initially compressed to 3.5 kbar (at 57 degrees C, pH 7.4). Decompression led to the formation of amyloid fibrils, protofibrils, or globular aggregates, as indicated by light scattering, thioflavin T fluorescence, and transmission electron microscopy analysis. Increased 1-anilinonaphthalene-8-sulfonate binding to the proteins was also observed, indicating exposure of hydrophobic surface area. Thus, pressure appears to induce a conformational state of lysozyme that aggregates readily upon decompression. These results support the notion that amyloid aggregation results from the formation of partially unfolded protein conformations and suggest that pressure may be a useful tool for the generation of the amyloidogenic conformations of lysozyme and other proteins.
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PMID:Formation of amyloid aggregates from human lysozyme and its disease-associated variants using hydrostatic pressure. 1515 66

It is well established that the rate of formation of fibrils by amyloidogenic proteins is enhanced by the addition of preformed fibrils, a phenomenon known as seeding. We show that the efficiency of seeding fibril formation from solutions of hen lysozyme by a series of other proteins depends strongly on the similarity of their sequences. This observation is consistent with the importance of long-range interactions in stabilizing the core structure of amyloid fibrils and may be associated with the existence of a species barrier observed in the transmissible spongiform encephalopathies. In addition, it is consistent with the observation of a single dominant type of protein in the deposits associated with each form of amyloid disease.
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PMID:Observation of sequence specificity in the seeding of protein amyloid fibrils. 1521 33

Amyloid fibrils obtained after incubating hen egg-white lysozyme (HEWL) at pH 2.0 and 65 degrees C for extended periods of time have been found to consist predominantly of fragments of the protein corresponding to residues 49-100, 49-101, 53-100 and 53-101, derived largely from the partial acid hydrolysis of Asp-X peptide bonds. These internal fragments of HEWL encompass part of the beta-domain and all the residues forming the C-helix in the native protein, and contain two internal disulfide bridges Cys64-Cys80 and Cys76-Cys94. The complementary protein fragments, including helices A, B and D of the native protein, are not significantly incorporated into the network of fibrils, but remain largely soluble, in agreement with their predicted lower propensities to aggregate. Further analysis of the properties of different regions of HEWL to form amyloid fibrils was carried out by studying fragments produced by limited proteolysis of the protein by pepsin. Here, we show that only fragment 57-107, but not fragment 1-38/108-129, is able to generate well-defined amyloid fibrils under the conditions used. This finding is of particular importance, as the beta-domain and C-helix of the highly homologous human lysozyme have been shown to unfold locally in the amyloidogenic variant D67H, which is associated with the familial cases of systemic amyloidosis linked to lysozyme deposition. The identification of the highly amyloidogenic character of this region of the polypeptide chain provides strong support for the involvement of partially unfolded species in the initiation of the aggregation events that lead to amyloid deposition in clinical disease.
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PMID:A highly amyloidogenic region of hen lysozyme. 1523 74

Transthyretin, beta(2)-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of alpha-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. In all beta-sheet proteins, transthyretin and beta(2)-microglobulin, alpha-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, alpha-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of alpha-pleated sheet structure may be a common conformational transition in amyloidosis.
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PMID:Pauling and Corey's alpha-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease. 1528 May 48

In amyloid diseases, it is not evident which protein aggregates induce cell death via specific molecular mechanisms and which cause damage because of their mass accumulation and mechanical properties. We showed that equine lysozyme assembles into soluble amyloid oligomers and protofilaments at pH 2.0 and 4.5, 57 degrees C. They bind thioflavin-T and Congo red similar to common amyloid structures, and their morphology was monitored by atomic force microscopy. Molecular volume evaluation from microscopic measurements allowed us to identify distinct types of oligomers, ranging from tetramer to octamer and 20-mer. Monomeric lysozyme and protofilaments are not cytotoxic, whereas the oligomers induce cell death in primary neuronal cells, primary fibroblasts, and the neuroblastoma IMR-32 cell line. Cytotoxicity was accessed by ethidium bromide staining, MTT reduction, and TUNEL assays. Primary cultures were more susceptible to the toxic effect induced by soluble amyloid oligomers than the neuroblastoma cell line. The cytotoxicity correlates with the size of oligomers; the sample incubated at pH 4.5 and containing larger oligomers, including 20-mer, appears to be more cytotoxic than the lysozyme sample kept at pH 2.0, in which only tetramers and octamers were found. Soluble amyloid oligomers may assemble into rings; however, there was no correlation between the quantity of rings in the sample and its toxicity. The cytotoxicity of transient oligomeric species of the ubiquitous protein lysozyme indicates that this is an intrinsic feature of protein amyloid aggregation, and therefore soluble amyloid oligomers can be used as a primary therapeutic target and marker of amyloid disease.
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PMID:Does the cytotoxic effect of transient amyloid oligomers from common equine lysozyme in vitro imply innate amyloid toxicity? 1557 61

The dissociation and reassociation processes of amyloid protofibrils initiated by pressure-jump have been monitored with real-time (1)H NMR spectroscopy using an intrinsically denatured disulfide-deficient variant of hen lysozyme. Upon pressure-jump up to 2 kbar, the matured protofibrils grown over several months become fully dissociated into monomers within a few days. Upon pressure-jump down to 30 bar, the dissociated monomers immediately start reassociating. The association and dissociation cycle can be repeated reproducibly by alternating pressure, establishing a notion that the protofibril formation is simply a slow kinetic process toward thermodynamic equilibrium. The outstanding simplicity and effectiveness of pressure in controlling the protofibril formation opens a new route for investigating mechanisms of amyloid fibril-forming reactions. The noted variation in the pressure-induced dissociation rate with the progress of the association reaction suggests multiple mechanisms for the elongation of the protofibril. The disulfide-deficient hen lysozyme offers a particularly simple model system for thermodynamic and kinetic studies of protofibril formation as well as for screening drugs for amyloidosis.
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PMID:Pressure-jump NMR study of dissociation and association of amyloid protofibrils. 1590 35

Mutations in a number of plasma proteins, including transthyretin, apolipoprotein AI, fibrinogen Aalpha-chain, lysozyme, and apolipoprotein AII, are associated with hereditary systemic amyloidosis. Transthyretin amyloidosis is the most common and is usually associated with peripheral neuropathy. Mutations in the other proteins usually have no neuropathic consequences and, instead, cause principally renal and cardiac amyloidosis. Only the apolipoprotein AI glycine 26 arginine mutation may cause peripheral neuropathy and then in only some of the kindreds with this disease. This review is concerned with the non-neuropathic hereditary systemic amyloidoses. It strives to present a synopsis of the present day knowledge of these diseases including each feature of each precursor protein and its mutations; the clinical phenotype of the disease; and suggestions for treatment when feasible. The main objective is to increase awareness of these autosomal dominant diseases, enhance the chances of early diagnosis, enhance the physician's and subsequently the patient's knowledge of each disease, and finally emphasize the need for more research to find ways to treat or prevent these diseases.
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PMID:Ostertag revisited: the inherited systemic amyloidoses without neuropathy. 1601 83

T70N human lysozyme is the only known naturally occurring destabilised lysozyme variant that has not been detected in amyloid deposits in human patients. Its study and a comparison of its properties with those of the amyloidogenic variants of lysozyme is therefore important for understanding the determinants of amyloid disease. We report here the X-ray crystal structure and the solution dynamics of T70N lysozyme, as monitored by hydrogen/deuterium exchange and NMR relaxation experiments. The X-ray crystal structure shows that a substantial structural rearrangement results from the amino acid substitution, involving residues 45-51 and 68-75 in particular, and gives rise to a concomitant separation of these two loops of up to 6.5A. A marked decrease in the magnitudes of the generalised order parameter (S2) values of the amide nitrogen atom, for residues 70-74, shows that the T70N substitution increases the flexibility of the peptide backbone around the site of mutation. Hydrogen/deuterium exchange protection factors measured by NMR spectroscopy were calculated for the T70N variant and the wild-type protein. The protection factors for many of backbone amide groups in the beta-domain of the T70N variant are decreased relative to those in the wild-type protein, whereas those in the alpha-domain display wild-type-like values. In pulse-labelled hydrogen/deuterium exchange experiments monitored by mass spectrometry, transient but locally cooperative unfolding of the beta-domain of the T70N variant and the wild-type protein was observed, but at higher temperatures than for the amyloidogenic variants I56T and D67H. These findings reveal that such partial unfolding is an intrinsic property of the human lysozyme structure, and suggest that the readiness with which it occurs is a critical feature determining whether or not amyloid deposition occurs in vivo.
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PMID:Rationalising lysozyme amyloidosis: insights from the structure and solution dynamics of T70N lysozyme. 1612 26

Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross-beta aggregates and deposit as amyloid. Hereditary amyloidoses are particularly interesting as they help to understand how changes in the primary structure of an otherwise non-amyloidogenic protein contribute to amyloidogenesis. Here we report on a novel form of systemic ALys amyloidosis, caused by compound heterozygosity in exon 2 (p.T70N) and exon 4 (p.W112R) of the lysozyme gene (LYZ), with both mutations being present on the same allele. This type of hereditary ALys amyloidosis is characterized by extended amyloid deposits in the upper gastrointestinal tract, entire colon, and kidney, leading to gastrointestinal bleeding. Both mutations are probably effective in disease manifestation. The novel mutation at position 112 in the mature protein is located within the alpha-helical domain of the protein and therefore outside the cluster of residues that has so far been implicated in ALys amyloidosis. Taken together with the p.T70N mutation, this results in a lysozyme species where the correct folding of various protein domains is probably impaired and increases the propensity of amyloid fibril formation. Interestingly, this form of ALys amyloidosis is also characterized by the occurrence of proteolytic fragments of lysozyme in the amyloid deposits.
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PMID:ALys amyloidosis caused by compound heterozygosity in exon 2 (Thr70Asn) and exon 4 (Trp112Arg) of the lysozyme gene. 1632 1


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