Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca2+ stabilization

Chen, Cidi; Huff, Mary E.; Matteson, Jeanne; Page, Lesley J.; Phillips, Rebecca A.; Balch, William E.

doi:10.1093/emboj/20.22.6277

Cited by 127 publications

(115 citation statements)

References 74 publications

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“…[1][2][3][4][5][6][7][8][9][10]23,[33][34][35][36][37][43][44][45] The prevention of amyloidogenesis by a kinetic stabilizer approach has recently been demonstrated to halt the progression of nervous system degeneration in familial amyloid polyneuropathy associated with the amyloidogenesis of transthyretin. Thus, it is logical that the removal of protein aggregates would be crucial for protein homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were injected in 100% H 2 O, 0.03% NH 4 OH on a Phenomenex Gemini-NX C18 column and eluted with a linear gradient of 50% methanol, 50% isopropanol, and 0.03% NH 4 OH. Resulting Ab 1-40 or 8 kDa gelsolin peak areas (220 nm absorbance) were quantified and normalized to a standard curve (buffer alone disaggregation negative control).…”

Section: Proteolysis Assaymentioning

confidence: 99%

“…Many age-related diseases (including Alzheimer's disease, the transthyretin amyloidoses, Parkinson's disease, Huntington's disease, and familial amyloidosis of Finnish type) are associated with amyloidogenesis, a process by which proteins misassemble or misfold and misassemble into both soluble and insoluble cross-b-sheet fibrillar aggregates called amyloid. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Amyloid is toxic when applied exogenously to or when formed within cultured cells. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Mouse and C. elegans models of amyloid diseases show that the cytotoxicity associated with amyloidogenesis increases with organismal age.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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The formation of amyloid, a cross-b-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils composed of amyloid b (Ab) 1-40 or the 8 kDa plasma gelsolin fragment. The mammalian disaggregase activity is sensitive to proteinase K digestion and can be uncoupled from proteolysis activity using a protease inhibitor cocktail. Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Proteolysis Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery and characterization of a mammalian amyloid disaggregation activity

Murray¹,

Solomon²,

Wang³

et al. 2010

Protein Science

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“…The conformational alterations within domain 2 of D187N/Y gelsolin render it susceptible to aberrant cleavage by furin in the slightly acidic trans-Golgi compartment yielding a secreted 68 kDa fragment referred to as C68 (5,6). C68 is subsequently cleaved by a membrane associated type I matrix metalloprotease located proximal to the extracellular matrix (ECM) where amyloid deposition is observed in patients (7).…”

mentioning

confidence: 99%

Heparin Accelerates Gelsolin Amyloidogenesis

et al. 2006

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The chemical environment of the extracellular matrix may influence the tissue-selective deposition observed there in gelsolin amyloid disease. Previously, we have identified the proteases that generate the amyloidogenic fragments from the full length gelsolin variants, and demonstrated that heparin is capable of accelerating gelsolin amyloidogenesis. Herein, we identify the structural features of heparin that promote the 8 kDa disease-associated gelsolin fragments (residues 173-243) generated at the cell surface to form amyloid. In conjunction with electron microscopy analyses, our kinetic studies demonstrate that heparin efficiently accelerates the formation of gelsolin amyloid by enabling intermolecular β-sheet formation. The use of heparin analogues reveal that sulfation is important in accelerating amyloidogenesis and that the extent of acceleration is proportional to the molecular weight of heparin. In addition, heparin accelerated aggregation at both early and late stages of amyloidogenesis. Dynamic light scattering coupled to size exclusion chromatography showed that heparin promotes the formation of soluble aggregates. Collectively, these data reveal that heparin templates fibril formation and affords solubility to the aggregating peptides through its sulfated structure. By extension, the biochemical results herein suggest that tissue-selective deposition characteristic of the gelsolin amyloidoses are likely influenced by the extracellular localization of distinct glycosaminoglycans.Amyloid diseases are characterized by the extracellular deposition of a given protein into a variety of structures, including cross β-sheet-rich fibrillar aggregates called amyloid. More than twenty non-homologous human proteins become amyloidogenic later in life. The clinically most important example is the amyloid β-peptide (Aβ) 1 , the deposits of which are associated with Alzheimer's disease. Many amyloid diseases exhibit distinct tissue-selective deposition of a given amyloidenic protein-the exact tissue targeted being dependent on the † We thank the Skaggs Institute of Chemical Biology, the Lita Annenberg Hazen Foundation and the National Institutes of Health (grants: AG18917, HL62244, HL52622 and GM038060) for financial support. * Corresponding author: tel: +1-858-784-9880; fax: +1-858-784-9899; email: jkelly@scripps.edu. Supporting Information Available: (1) Pre-treated D187N gelsolin173-243 fragments were analyzed to confirm a monomeric starting structure and the analytical ultracentrifugation, atomic force microscopy analyses of these samples are shown. (2) WT and D187Y gelsolin173-243 fragments were subjected to amyloid formation plate-reader assays as controls. The amyloid formation profiles of WT gelsolin173-243 are shown in the presence of various GAGs and heparin derivatives. The D187Y gelsolin173-243 only aggregated at acidic (pH 5) conditions. (3) Dextran sulfate and polyglutamic acid did not accelerate D187N gelsolin173-243 amyloidogenesis in the TfT fluorescence assays shown. (4) Full, unadjusted TE...

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“…Thus, amyloid formation does not appear to be restricted to a small number of protein sequences but is rather a property common to many, if not all, polypeptide chains. Recent experimental data show that some human genetic amyloid diseases are due to point mutations that cause incomplete protein folding, thereby increasing the propensity of the polypeptide chain to aggregate (16,17).…”

mentioning

confidence: 99%

Tryptophanyl Substitutions in Apomyoglobin Determine Protein Aggregation and Amyloid-like Fibril Formation at Physiological pH

Sirangelo

Malmo

Casillo

et al. 2002

Journal of Biological Chemistry

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Myoglobin is an ␣-helical globular protein that contains two highly conserved tryptophan residues located at positions 7 and 14 in the N-terminal region of the protein. Replacement of both indole residues with phenylalanine residues, i.e. W7F/W14F, results in the expression of an unstable, not correctly folded protein that does not bind the prosthetic group. Here we report data (Congo red and thioflavine T binding assay, birefringence, and electron microscopy) showing that the double Trp/Phe replacements render apomyoglobin molecules highly susceptible to aggregation and amyloid-like fibril formation under physiological conditions in which most of the wild-type protein is in the native state. In refolding experiments, like the wild-type protein, the W7F/W14F apomyoglobin mutant formed a soluble, partially folded helical state between pH 2.0 and pH 4.0. A pH increase from 4.0 to 7.0 restored the native structure only in the case of the wild-type protein and determined aggregation of W7F/W14F. The circular dichroism spectrum recorded immediately after neutralization showed that the polypeptide consists mainly of ␤-structures. In conclusion, under physiological pH conditions, some mutations that affect folding may cause protein aggregation and the formation of amyloid-like fibrils.Such chronic disorders as Alzheimer's disease, senile systemic amyloidosis, transmissible spongiform encephalopathies, and dialysis-related amyloidosis are characterized by the extracellular deposition of insoluble protein aggregates known as amyloid fibrils (1-6). About 20 proteins are now known to be involved in the generation of amyloid in vivo. Fibril formation is initiated in vitro under conditions that stabilize partially unfolded soluble intermediates of the native proteins either after the partial destabilization of physiologically folded proteins in the case of globular proteins (7) or after the partial stabilization (i.e. folding) of random coil polypeptide chains in the case of natively unfolded proteins (8). Despite substantial differences in both sequence and length (from 40 to 250 residues), all the proteins responsible for amyloid deposition form fibrils composed of ␤-strands oriented perpendicularly to the long axis of the fibril (9). Electron microscopy shows that the fibrils are straight and unbranched and are 40 -120 Å in diameter (9, 10). Also proteins not known to be associated with amyloid disease may form amyloid fibrils under in vitro conditions that favor partially folded states (11-15). These states are more prone to aggregation than the native state because hydrophobic residues, which are largely buried within the core of the native protein, become more exposed upon partial unfolding. The way in which proteins aggregate in the test tube is remarkably similar to how proteins form the so-called "amyloid" deposits. Even myoglobin, an ordinary all-␣ globular protein, can form fibrils containing ␤-strands under experimental conditions that favor the formation of partially folded states (15). Thus, amyloid formation d...

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Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca2+ stabilization

Cited by 127 publications

References 74 publications

Discovery and characterization of a mammalian amyloid disaggregation activity

Discovery and characterization of a mammalian amyloid disaggregation activity

Heparin Accelerates Gelsolin Amyloidogenesis

Tryptophanyl Substitutions in Apomyoglobin Determine Protein Aggregation and Amyloid-like Fibril Formation at Physiological pH

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