Plasminogen activation triggers transthyretin amyloidogenesis in vitro.

The Journal of Biological Chemistry
P Patrizia MangioneVittorio Bellotti

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. 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 co...Continue Reading

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Citations

Nov 28, 2018·Neurodegenerative Disease Management·Arnt V KristenLaura Obici
Nov 30, 2019·Current Heart Failure Reports·Sandra IhneStefan Störk
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Methods Mentioned

BETA
light scattering
AFM
antisense oligonucleotide
protein assay
light
atomic force microscopy

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