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Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils

Raimondi, S; Mangione, PP; Verona, G; Canetti, D; Nocerino, P; Marchese, L; Piccarducci, R; ... Bellotti, V; + view all (2020) Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils. Journal of Biological Chemistry , 295 (33) pp. 11379-11387. 10.1074/jbc.RA120.014026. Green open access

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Abstract

Systemic amyloidosis caused by extracellular deposition of insoluble fibrils derived from the pathological aggregation of circulating proteins, such as transthyretin, is a severe and usually fatal condition. Elucidation of the molecular pathogenic mechanism of the disease and discovery of effective therapies still represents a challenging medical issue. The in vitro preparation of amyloid fibrils that exhibit structural and biochemical properties closely similar to those of natural fibrils is central to improving our understanding of the biophysical basis of amyloid formation in vivo and may offer an important tool for drug discovery. Here, we compared the morphology and thermodynamic stability of natural transthyretin fibrils with those of fibrils generated in vitro using either the common acidification procedure or primed by limited selective cleavage by plasmin. The free energies for fibril formation were -12.36 kcal mol-1, -8.10 kcal mol-1 and -10.61 kcal mol-1, respectively. The fibrils generated via plasmin cleavage were more stable than those prepared at low pH and were thermodynamically and morphologically similar to natural fibrils extracted from human amyloidotic tissue. Determination of thermodynamic stability is an important tool that is complementary to other methods for structural comparison between ex vivo fibrils and fibrils generated in vitro Our finding that fibrils created via an in vitro amyloidogenic pathway are structurally similar to ex vivo human amyloid fibrils does not necessarily establish that the fibrillogenic pathway is the same for both, but it narrows the current knowledge gap between in vitro models and in vivo pathophysiology.

Type: Article
Title: Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.RA120.014026
Publisher version: http://dx.doi.org/10.1074/jbc.RA120.014026
Language: English
Additional information: This is an Open Access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
Keywords: V122I TTR mutation, amyloid, fibril, mechano-enzymatic mechanism, protein aggregation, protein misfolding, protein stability, systemic amyloidosis, thermodynamics, 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/10103195
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