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Query: UNIPROT:P06889 (Mol)
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A variety of diseases result because of misfolded protein that deposits in extracellular space in the body. These deposits can be amorphous (disordered) or fibrillar (ordered). Inclusion bodies are an example of amorphous aggregates, and amyloid fibril is an example of fibrillar or ordered aggregates. In this chapter, we discuss a class of diseases caused by fibrillar aggregate deposits or amyloid fibrils called amyloidosis. We also review mechanisms by which different proteins misfold to form amyloid fibrils. Each amyloid fibril formed from a different protein causes a different disease by affecting a different organ in the body. However, the characteristics of different amyloid fibrils, namely structure and morphology, observed by electron microscopy and X-ray fiber diffraction appear to be quite similar in nature. We present therapeutic strategies developed to eliminate amyloid fibril formation. These strategies could possibly avert a whole class of fatal diseases caused by amyloid fibril deposition owing to similar characteristics of the amyloid fibrils.
Methods Mol Biol 2005
PMID:Protein amyloidose misfolding: mechanisms, detection, and pathological implications. 1565 95

Many proteins form amyloid-like fibrils in vitro under conditions that favour the population of partially folded conformations or denatured state ensembles. Characterising the structural and dynamic properties of these states is crucial towards understanding the mechanisms of self-assembly in amyloidosis. The aggregation of beta2-microglobulin (beta2m) into amyloid fibrils in vivo occurs in the condition known as dialysis-related amyloidosis (DRA) and the protein has been shown to form amyloid-like fibrils under acidic conditions in vitro. We have used a number of 1H-15N nuclear magnetic resonance (NMR) experiments in conjunction with site-directed mutagenesis to study the acid-unfolded state of beta2m. 15N NMR transverse relaxation experiments reveal that the acid-denatured ensemble, although predominantly unfolded at the N and C termini, contains substantial non-native structure in the central region of the polypeptide chain, stabilised by long-range interactions between aromatic residues and by the single disulphide bond. Relaxation dispersion studies indicate that the acid-unfolded ensemble involves two or more distinct species in conformational equilibrium on the micro- to millisecond time-scale. One of these species appears to be hydrophobically collapsed, as mutations in an aromatic-rich region of the protein, including residues that are solvent-exposed in the native protein, disrupt this structure and cause a consequent decrease in the population of this conformer. Thus, acid-unfolded beta2m consists of a heterogeneous ensemble of rapidly fluctuating species, some of which contain stable, non-native hydrophobic clusters. Given that amyloid assembly of beta2m proceeds with lag kinetics under the conditions of this study, a rarely populated species such as a conformer with non-native aromatic clustering could be key to the initiation of amyloidosis.
J Mol Biol 2005 Feb 11
PMID:Dynamics in the unfolded state of beta2-microglobulin studied by NMR. 1566 44

A range of disorders such as Alzheimer's disease and type II diabetes have been linked to protein misfolding and aggregation. Transthyretin is an amyloidogenic protein which is involved in familial amyloid polyneuropathy, the most common form of systemic amyloid disease. A peptide fragment of this protein, TTR105-115, has been shown to form well-defined amyloid fibrils in vitro. In this study, the stability of amyloid fibrils towards high hydrostatic pressure has been investigated by Fourier transform infrared spectroscopy. Information on the morphology of the species exposed to high hydrostatic pressure was obtained by atomic force microscopy. The species formed early in the aggregation process were found to be dissociated by relatively low hydrostatic pressure (220 MPa), whereas mature fibrils are pressure insensitive up to 1.3 GPa. The pressure stability of the mature fibrils is consistent with a fibril structure in which there is an extensive hydrogen bond network in a tightly packed environment from which water is excluded. The fact that early aggregates can be dissociated by low pressure suggests, however, that hydrophobic and electrostatic interactions are the dominant factors stabilizing the species formed in the early stages of fibril formation.
J Mol Biol 2005 Apr 15
PMID:High hydrostatic pressure dissociates early aggregates of TTR105-115, but not the mature amyloid fibrils. 1578 51

beta(2)-Microglobulin (beta2-m), a light chain of the major histocompatibility complex type I, is also found as a major component of amyloid fibrils formed in dialysis-related amyloidosis. Denaturation of beta2-m is considered to initiate the formation of fibrils. To clarify the mechanism of fibril formation, it is important to characterize the intermediate conformational states at the atomic level. Here, we investigated the refolding of beta2-m from the acid-unfolded state by heteronuclear magnetic resonance and circular dichroism spectroscopies. At low temperature, beta2-m refolded slowly, accumulating a rate-limiting intermediate with non-native chemical shift dispersions for several residues, but with compactness and secondary structures similar to those of the native protein. beta2-m has a cis proline residue at Pro32, located on the turn connecting the betaB and betaC strands. The slow refolding phase disappeared upon mutation of Pro32 to Val, indicating that Pro32 is responsible for the accumulation of the intermediate. The distribution of the perturbed residues in the intermediate suggests that the non-native prolyl peptide bond of Pro32 affects large areas of the molecule. A cis proline residue is common to various immunoglobulin domains involved in amyloidosis, implying that a non-native prolyl peptide bond that might occur under physiological conditions is related to the amyloidogenicity of these immunoglobulin domains.
J Mol Biol 2005 Apr 29
PMID:Nuclear magnetic resonance characterization of the refolding intermediate of beta2-microglobulin trapped by non-native prolyl peptide bond. 1581 75

Cerebral amyloid angiopathy is a common pathological feature of patients with Alzheimer's disease (AD) and it is also the hallmark of individuals with a rare autosomal dominant disorder known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. We have shown previously that wild type A(beta) peptides are anti-angiogenic both in vitro and in vivo and could contribute to the compromised cerebrovascular architecture observed in AD. In the present study, we investigated the potential anti-angiogenic activity of the Dutch A(beta)(1-40) (E22Q) peptide. We show that compared to wild type A(beta), freshly solubilized Dutch A(beta) peptide more potently inhibits the formation of capillary structures induced by plating human brain microvascular endothelial cells onto a reconstituted basement membrane. Aggregated/fibrillar preparations of wild type A(beta) and Dutch A(beta) do not appear to be anti-angiogenic in this assay. The stronger anti-angiogenic activity of the Dutch A(beta) compared to wild type A(beta) appears to be related to the increased formation of low molecular weight A(beta) oligomers in the culture medium surrounding human brain microvascular endothelial cells. Using oligonucleotide microarray analysis of human brain microvascular endothelial cells, followed by a genome-scale computational analysis with the Ingenuity Pathways Knowledge Base, networks of genes affected by an anti-angiogenic dose of Dutch A(beta) were identified. This analysis highlights that several biological networks involved in angiogenesis, tumorigenesis, atherosclerosis, cellular migration and proliferation are disrupted in human brain microvascular endothelial cells exposed to Dutch A(beta). Altogether, these data provide new molecular clues regarding the pathological activity of Dutch A(beta) peptide in the cerebrovasculature.
Brain Res Mol Brain Res 2005 May 20
PMID:Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells. 1589 5

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.
J Mol Biol 2005 Jun 24
PMID:Pressure-jump NMR study of dissociation and association of amyloid protofibrils. 1590 35

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.
Cell Mol Life Sci 2005 Aug
PMID:Chromosome 13 dementias. 1596 64

The characterization of proteins in their native state is essential for the understanding of patho-genic isoforms. A variant of the cysteine protease inhibitor cystatin C is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). In order to study the nature of the bio-physical changes owing to the Leu68Gln substitution in cystatin C, we have developed a purification procedure of human cystatin C in its native state. The protein is isolated from media of stably transfected tissue culture cells using physiological conditions that preclude protein denaturation. The importance of mild purification conditions is underscored by the finding that denaturation of the wild-type and variant proteins facilitates a similar folding of both molecules, diminishing their differences in structure and biophysical properties. Following native purification conditions, variant cystatin C has a distinct structure compared to the wild-type protein.
Methods Mol Biol 2005
PMID:Purification of human wild-type or variant cystatin C from conditioned media of transfected cells. 1598 Jun 5

Protein AA, the major amyloid fibril protein in reactive (secondary) systemic amyloidosis is derived from the acute phase reactant liver-produced apolipoprotein serum AA (SAA) by proteolytic cleavage, usually in the C-terminal half of the 104 amino acid residues long precursor. The cleavage points in SAA vary between patients and the deposited protein AA is often quite heterogeneous. In this chapter, we describe methods to extract amyloid fibrils and to purify protein AA by sequential gel filtration. Further purification of subspecies of protein AA is best achieved by the use of differences in charge and chromatofocusing is described as the method of choice. Analytic methods include sodium dodecylsulfate polyacrylamide gel electrophoresis and analytic isoelectric focusing.
Methods Mol Biol 2005
PMID:Purification of amyloid protein AA subspecies from amyloid-rich human tissues. 1598 Jun 8

Transthyretin is the major amyloid fibril protein in many forms of familial systemic amyloidosis where a missense mutation creates an amyloidogenic protein, and in senile systemic amyloidosis in which wild-type transthyretin aggregates into amyloid fibrils. The amyloid deposits may consist of full-length transthyretin but is very often, in senile systemic amyloidosis always, a mixture of full-length transthyretin and C-terminal transthyretin fragments. The amyloid fibril protein mixture can be purified by extraction of fibrils followed by sequential gel filtration after solubilization in a solution of guanidine hydrochloride. Since the C-terminal transthyretin fragments lack cysteine residues, a method to separate full-length transthyretin from fragments by covalent chromatography has been developed.
Methods Mol Biol 2005
PMID:Purification of transthyretin and transthyretin fragments from amyloid-rich human tissues. 1598 Jun 9


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