Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis
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- P. Patrizia Mangione
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Riccardo Porcari
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Julian D. Gillmore
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Piero Pucci
- Department of Chemical Sciences and
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- Maria Monti
- Department of Chemical Sciences and
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- Mattia Porcari
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy;
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- Sofia Giorgetti
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy;
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- Loredana Marchese
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy;
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- Sara Raimondi
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy;
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- Louise C. Serpell
- School of Life Sciences, University of Sussex, Falmer BN1 9QG, United Kingdom;
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- Wenjie Chen
- Laboratory of Protein Crystallography, Centre for Amyloidosis and Acute Phase Proteins, and
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- Annalisa Relini
- Department of Physics, University of Genoa, 16146 Genoa, Italy; and
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- Julien Marcoux
- Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom
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- Innes R. Clatworthy
- Electron Microscopy Unit, University College London, London NW3 2PF, United Kingdom;
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- Graham W. Taylor
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Glenys A. Tennent
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Carol V. Robinson
- Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom
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- Philip N. Hawkins
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Monica Stoppini
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy;
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- Stephen P. Wood
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Mark B. Pepys
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
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- Vittorio Bellotti
- Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine,
説明
<jats:title>Significance</jats:title><jats:p>Transthyretin, a normal circulating plasma protein, is inherently amyloidogenic. It forms abnormal, insoluble, extracellular amyloid fibrils in the elderly, sometimes causing structural and functional damage leading to disease, senile amyloidosis. More than 100 different point mutations in the transthyretin gene cause earlier adult-onset, autosomal-dominant, fatal, hereditary amyloidosis. The transthyretin variant Ser52Pro is responsible for the most aggressive known clinical phenotype. Here we identify the crucial pathogenic role of specific proteolytic cleavage at residue 48 in triggering fibril formation by this variant. Genuine amyloid fibril formation in vitro is much more extensive than previously reported for wild-type transthyretin or any other transthyretin variant. Characterization of the fibrillogenic effect of this cleavage powerfully informs drug design and targeting for transthyretin amyloidosis.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 111 (4), 1539-1544, 2014-01-13
Proceedings of the National Academy of Sciences