Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta(2)-Microglobulin (beta(2)m) is one of over 20 proteins known to be involved in human amyloid disease. Peptides equivalent to each of the seven beta-strands of the native protein, together with an eighth peptide (corresponding to the most stable region in the amyloid precursor conformation formed at pH 3.6, that includes residues in the native strand E plus the eight succeeding residues (named peptide E')), were synthesised and their ability to form fibrils investigated. Surprisingly, only two sequences, both of which encompass the region that forms strand E in native beta(2)m, are capable of forming amyloid-like fibrils in vitro. These peptides correspond to residues 59-71 (peptide E) and 59-79 (peptide E') of intact beta(2)m. The peptides form fibrils under the acidic conditions shown previously to promote amyloid formation from the intact protein (pH <5 at low and high ionic strength), and also associate to form fibrils at neutral pH. Fibrils formed from these two peptides enhance fibrillogenesis of the intact protein. No correlation was found between secondary structure propensity, peptide length, pI or hydrophobicity and the ability of the peptides to associate into amyloid-like fibrils. However, the presence of a relatively high content of aromatic side-chains correlates with the ability of the peptides to form amyloid fibrils. On the basis of these results we propose that residues 59-71 may be important in the self-association of partially folded beta(2)m into amyloid fibrils and discuss the relevance of these results for the assembly mechanism of the intact protein in vitro.
J Mol Biol 2003 Jan 10
PMID:Amyloid-forming peptides from beta2-microglobulin-Insights into the mechanism of fibril formation in vitro. 1248 93

Immunohistochemistry (IHC) is frequently used to detect plasma cell (PC) or B cell monoclonality in histologic sections, but its interpretation is often confounded by background staining. We evaluated a new automated method for colorimetric in situ hybridization (CISH) detection of clonality in PC dyscrasias and small B cell lymphomas. Cases of PC dyscrasia included multiple myeloma (MM; 31 cases), plasmacytoma (seven cases), or amyloidosis (one case), while cases of lymphoma included small lymphocytic (three cases), marginal zone (four cases), lymphoplasmacytic (three cases), and mantle cell lymphomas (three cases). Tissue sections were stained for kappa and lambda light chains by IHC and for light chain mRNA by automated CISH using haptenated probes. Twenty-eight of 31 MM cases had detectable light chain restriction by IHC. Thirty of 31 MM cases demonstrated light chain restriction by CISH, including 2 cases with uninterpretable IHC and one case of nonsecretory myeloma, which was negative for light chains by IHC. Seven of 7 plasmacytoma cases had detectable light chain restriction by CISH, including one case of nonsecretory plasmacytoma in which IHC was noninformative. Automated CISH demonstrated monoclonality in 9 of 13 cases of B cell non-Hodgkin lymphoma and had a slightly higher sensitivity than IHC (6 of 13 cases), especially in cases of lymphoplasmacytic and marginal zone lymphoma. Overall, there were no discrepancies in light chain restriction results between IHC, CISH, or serum paraprotein analysis. Automated CISH is useful in detecting light chain expression in paraffin sections and appeared superior to IHC for light chain detection in PC dyscrasias and B cell non-Hodgkin lymphomas, predominantly due to lack of background staining.
Diagn Mol Pathol 2003 Mar
PMID:Automated colorimetric in situ hybridization (CISH) detection of immunoglobulin (Ig) light chain mRNA expression in plasma cell (PC) dyscrasias and non-Hodgkin lymphoma. 1260 31

The formation of amyloid aggregates is the hallmark of the amyloidogenic diseases. Transthyretin (TTR) is involved in senile systemic amyloidosis (wild-type protein) and familial amyloidotic polyneuropathy (point mutants). Through the use of high hydrostatic pressure (HHP), we compare the stability among wild-type (wt) TTR, two disease-associated mutations (V30M and L55P) and a trans-suppressor mutation (T119M). Our data show that the amyloidogenic conformation, easily populated in the disease-associated mutant L55P, can be induced by a cycle of compression-decompression with the wt protein rendering the latter highly amyloidogenic. After decompression, the recovered wt structure has weaker subunit interactions (loosened tetramer, T(4)(*)) and presents a stability similar to L55P, suggesting that HHP induces a defective fold in the wt protein, converting it to an altered conformation already present in the aggressive mutant, L55P. On the other hand, glucose, a chemical chaperone, can mimic the trans-suppression mutation by stabilizing the native state and by decreasing the amyloidogenic potential of the wt TTR at pH 5.0. The sequence of pressure stability observed was: L55P<V30M<wt<<T119M. The pressure dissociation of L55P at 1 degrees C exhibited dependence on protein concentration, allowing us to assess the volume change of association and the free-energy change. After a cycle of compression-decompression at 37 degrees C and pH 5.6 or lower, all amyloidogenic variants underwent aggregation. Binding of bis-(8-anilinonaphthalene-1-sulfonate) (bis-ANS) revealed that the species formed under pressure retained part of its tertiary contacts (except T119M). However, at neutral pH, where aggregation did not take place after decompression, bis-ANS binding was absent. Thus, TTR has to experience this partially folded conformation to undergo aggregation after decompression. Overall, our studies provide evidence that amyloidogenesis correlates with less packed structures (larger volume changes) and high susceptibility to water infiltration. The hydration effects can be counteracted by osmolytes or by a specific mutation.
J Mol Biol 2003 May 09
PMID:Hydration and packing are crucial to amyloidogenesis as revealed by pressure studies on transthyretin variants that either protect or worsen amyloid disease. 1272 68

Current data suggest that globular domains may form amyloids via different mechanisms. Nevertheless, there are indications that the initiation of the process takes place invariably in the less stable segments of a protein domain. We have studied the sequence and structural conservation of beta(2)-microglobulin that deposits into fibrils in dialysis-related amyloidosis. The dataset includes 51 high-resolution non-redundant structures of the antibody constant domain-like proteins (C1) and 132 related sequences. We describe a set of 30 conserved residues. Among them, 23 are conserved structurally, 16 are conserved sequentially and nine are conserved both sequentially and structurally. Strands A (12-18), G (91-95) and D (45-55) are the less conserved and stable segments of the domain, while strands B (22-28), C (36-41), E (62-70) and F (78-83) are the conserved and stable segments. We find that the conserved residues form a cluster with a network of interactions. The observed pattern of conservation is consistent with experimental data including H/D exchange, urea denaturation and limited proteolysis that suggest that strands A and G do not participate in the amyloid fibril. Additionally, the low conservation of strand D is consistent with the observation that this strand may acquire different conformations as seen in crystal structures of bound and isolated beta(2)-microglobulin. We used a docking technique to suggest a model for a fibril via stacking of beta(2)-microglobulin monomers. Our analysis suggests that the favored monomer building block for fibril elongation is the conformation of the isolated beta(2)-microglobulin, without the beta-bulge on strand D and without strands A and G participating in the fibril beta-sheet structure. This monomer retains all the conserved residues and their network of interactions, increasing the likelihood of its existence in solution. The inter-strand interaction between the two (monomer) building blocks forms a new continuous beta-sheet such that addition of monomers results in a fibril model that has the characteristic cross-beta structure.
J Mol Biol 2003 Jun 27
PMID:Beta2-microglobulin amyloidosis: insights from conservation analysis and fibril modelling by protein docking techniques. 1281 10

The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than 20 degenerative conditions affecting either the central nervous system or a variety of peripheral tissues. As these conditions include Alzheimer's, Parkinson's and the prion diseases, several forms of fatal systemic amyloidosis, and at least one condition associated with medical intervention (haemodialysis), they are of enormous importance in the context of present-day human health and welfare. Much remains to be learned about the mechanism by which the proteins associated with these diseases aggregate and form amyloid structures, and how the latter affect the functions of the organs with which they are associated. A great deal of information concerning these diseases has emerged, however, during the past 5 years, much of it causing a number of fundamental assumptions about the amyloid diseases to be re-examined. For example, it is now apparent that the ability to form amyloid structures is not an unusual feature of the small number of proteins associated with these diseases but is instead a general property of polypeptide chains. It has also been found recently that aggregates of proteins not associated with amyloid diseases can impair the ability of cells to function to a similar extent as aggregates of proteins linked with specific neurodegenerative conditions. Moreover, the mature amyloid fibrils or plaques appear to be substantially less toxic than the pre-fibrillar aggregates that are their precursors. The toxicity of these early aggregates appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increases in free Ca2+ that eventually lead to apoptotic or necrotic cell death. The 'new view' of these diseases also suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses. In addition, cellular protection mechanisms, such as molecular chaperones and the protein degradation machinery, appear to be crucial in the prevention of disease in normally functioning living organisms. It also suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.
J Mol Med (Berl) 2003 Nov
PMID:Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. 1294 75

Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.
J Mol Neurosci 2003
PMID:Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. 1450 Oct 24

The ABri is a 34 residue peptide that is the major component of amyloid deposits in familial British dementia. In the amyloid deposits, the ABri peptide adopts aggregated beta-pleated sheet structures, similar to those formed by the Abeta peptide of Alzheimer's disease and other amyloid forming proteins. As a first step toward elucidating the molecular mechanisms of the beta-amyloidosis, we explored the ability of the environmental variables (pH and peptide concentration) to promote beta-sheet fibril structures for synthetic ABri peptides. The secondary structures and fibril morphology were characterized in parallel using circular dichroism, atomic force microscopy, negative stain electron microscopy, Congo red, and thioflavin-T fluorescence spectroscopic techniques. As seen with other amyloid proteins, the ABri fibrils had characteristic binding with Congo red and thioflavin-T, and the relative amounts of beta-sheet and amyloid fibril-like structures are influenced strongly by pH. In the acidic pH range 3.1-4.3, the ABri peptide adopts almost exclusively random structure and a predominantly monomeric aggregation state, on the basis of analytical ultracentrifugation measurements. At neutral pH, 7.1-7.3, the ABri peptide had limited solubility and produced spherical and amorphous aggregates with predominantly beta-sheet secondary structure, whereas at slightly acidic pH, 4.9, spherical aggregates, intermediate-sized protofibrils, and larger-sized mature amyloid fibrils were detected by atomic force microscopy. With aging at pH 4.9, the protofibrils underwent further association and eventually formed mature fibrils. The presence of small amounts of aggregated peptide material or seeds encourage fibril formation at neutral pH, suggesting that generation of such seeds in vivo could promote amyloid formation. At slightly basic pH, 9.0, scrambling of the Cys5-Cys22 disulfide bond occurred, which could lead to the formation of covalently linked aggregates. The presence of the protofibrils and the enhanced aggregation at slightly acidic pH is consistent with the behavior of other amyloid-forming proteins, which supports the premise that a common mechanism may be involved in protein misfolding and beta-amyloidosis.
J Mol Biol 2003 Nov 07
PMID:pH-dependent amyloid and protofibril formation by the ABri peptide of familial British dementia. 1458 96

Mutation of aspartic acid 187 to asparagine (D187N) or tyrosine (D187Y) in domain 2 of the actin-modulating protein gelsolin causes the neurodegenerative disease familial amyloidosis of Finnish type (FAF). These mutations render plasma gelsolin susceptible to aberrant proteolysis by furin in the trans-Golgi network, the initial proteolytic event in the formation of 71 and 53 residue fragments that assemble into amyloid fibrils. Ca(2+) binding stabilizes wild-type domain 2 gelsolin against denaturation and proteolysis, but the FAF variants are unable to bind and be stabilized by Ca(2+). Though the chain of events initiating FAF has been elucidated recently, uncertainty remains about the mechanistic details that allow the FAF variants to be processed. To test the hypothesis that impaired Ca(2+) binding in the D187 variants, but not other factors specific to residue 187, increases susceptibility to aberrant proteolysis and subsequent amyloidogenesis, we designed the gelsolin variant E209Q to remove a different Ca(2+) ligand from the same Ca(2+) site that is affected in the FAF variants. Here, we show that E209Q domain 2 does not bind Ca(2+) and is not stabilized against denaturation or furin proteolysis, analogous to the behavior exhibited by the FAF variants. Transfection of full-length E209Q into COS cells results in secretion of both the full-length and furin-processed fragments, as observed with D187N and D187Y. Mutation of the furin consensus sequence in D187N and E209Q gelsolin prevents cleavage during secretion, indicating that inhibition of proprotein convertases (furin) represents a viable therapeutic approach for the treatment of FAF. Mutations that diminish domain 2 Ca(2+) binding allow furin access to an otherwise protected cleavage site, initiating the proteolytic cascade that leads to gelsolin amyloidogenesis and FAF.
J Mol Biol 2003 Nov 14
PMID:Gelsolin domain 2 Ca2+ affinity determines susceptibility to furin proteolysis and familial amyloidosis of finnish type. 1459 4

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever, serositis, and a risk for AA amyloidosis. FMF is caused by mutations in the Mediterranean fever gene (MEFV), which is expressed in blood cells of the myelomonocytic differentiation pathway. We identified a novel mutation S1791 in exon 2 of MEFV in two members of a family of Turkish origin. In both cases, S1791 was in compound heterozygosity with MEFV mutation M694V, and the characteristic clinical syndrome of FMF including amyloidosis was found. The location of S1791 in exon 2 is of interest because (1) amyloidosis in FMF has previously been found to be strongly associated with compound exon 10 mutations and (2) it supports the notion that the mechanism causing FMF is connected to the cytoplasmic rather than nuclear function of the molecule.
Blood Cells Mol Dis
PMID:Familial Mediterranean fever with amyloidosis associated with novel exon 2 mutation (S1791) of the MEFV gene. 1463 45

Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a conformational change and form amyloid fibrils, in both acquired and hereditary forms of systemic amyloidosis. More than 80 TTR mutations have been associated with autosomal dominant amyloidosis, usually presenting with peripheral and autonomic neuropathy and/or cardiomyopathy. Major areas of research in TTR amyloidosis include: molecular mechanisms leading to fibril formation; mechanisms of fibril-induced cell death; modulators of phenotypic expression of the disease; and therapeutic strategies.
Expert Rev Mol Med 2002 May 14
PMID:Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies. 1498 80


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