Abstract
Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT 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. Wehave 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.
| Original language | English |
|---|---|
| Pages (from-to) | 14192-14199 |
| Number of pages | 8 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 37 |
| DOIs | |
| Publication status | Published - Jan 1 2018 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Plasminogen activation triggers transthyretin amyloidogenesis in vitro. / Mangione, P. Patrizia; Verona, Guglielmo; Corazza, Alessandra; Marcoux, Julien; Canetti, Diana; Giorgetti, Sofia; Raimondi, Sara; Stoppini, Monica; Esposito, Marilena; Relini, Annalisa; Canale, Claudio; Valli, Maurizia; Marchese, Loredana; Faravelli, Giulia; Obici, Laura; Hawkins, Philip N.; Taylor, Graham W.; Gillmore, Julian D.; Pepys, Mark B.; Bellotti, Vittorio.
In: Journal of Biological Chemistry, Vol. 293, No. 37, 01.01.2018, p. 14192-14199.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Plasminogen activation triggers transthyretin amyloidogenesis in vitro
AU - Mangione, P. Patrizia
AU - Verona, Guglielmo
AU - Corazza, Alessandra
AU - Marcoux, Julien
AU - Canetti, Diana
AU - Giorgetti, Sofia
AU - Raimondi, Sara
AU - Stoppini, Monica
AU - Esposito, Marilena
AU - Relini, Annalisa
AU - Canale, Claudio
AU - Valli, Maurizia
AU - Marchese, Loredana
AU - Faravelli, Giulia
AU - Obici, Laura
AU - Hawkins, Philip N.
AU - Taylor, Graham W.
AU - Gillmore, Julian D.
AU - Pepys, Mark B.
AU - Bellotti, Vittorio
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT 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. Wehave 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.
AB - Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT 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. Wehave 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.
UR - http://www.scopus.com/inward/record.url?scp=85053084151&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053084151&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.003990
DO - 10.1074/jbc.RA118.003990
M3 - Article
AN - SCOPUS:85053084151
VL - 293
SP - 14192
EP - 14199
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 37
ER -