Mangione, PP;
Verona, G;
Corazza, A;
Marcoux, J;
Canetti, D;
Giorgetti, S;
Raimondi, S;
... Bellotti, V; + view all
(2018)
Plasminogen activation triggers transthyretin amyloidogenesis in vitro.
Journal of Biological Chemistry
, 293
(37)
pp. 14192-14199.
10.1074/jbc.RA118.003990.
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Abstract
Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibres, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both wild type and genetic variants of the normal plasma protein, transthyretin (TTR), form amyloid but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano-enzymatic mechanism that generates abundant amyloid fibrils in vitro In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0, yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro Truncated and full length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors and for therapeutic innovation.
| Type: | Article |
|---|---|
| Title: | Plasminogen activation triggers transthyretin amyloidogenesis in vitro |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.RA118.003990 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.RA118.003990 |
| Language: | English |
| Additional information: | © 2018 Mangione et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0). |
| Keywords: | amyloid, amyloid fibrillogenesis, amyloidogenesis, fibril, mechano enzymatic mechanism, protease, protein aggregation, systemic amyloidosis, tissue plasminogen activator (tPA), transthyretin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10052869 |
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