Verona, G;
Raimondi, S;
Canetti, D;
Mangione, PP;
Marchese, L;
Corazza, A;
Lavatelli, F;
... Giorgetti, S; + view all
(2024)
Degradation versus fibrillogenesis, two alternative pathways modulated by seeds and glycosaminoglycans.
Protein Science
, 33
(3)
, Article e4931. 10.1002/pro.4931.
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Abstract
The mechanism that converts native human transthyretin into amyloid fibrils in vivo is still a debated and controversial issue. Commonly, non-physiological conditions of pH, temperature, or organic solvents are used in in vitro models of fibrillogenesis of globular proteins. Transthyretin amyloid formation can be achieved under physiological conditions through a mechano-enzymatic mechanism involving specific serine proteases such as trypsin or plasmin. Here, we investigate S52P and L111M transthyretin variants, both causing a severe form of systemic amyloidosis mostly targeting the heart at a relatively young age with heterogeneous phenotype among patients. Our studies on thermodynamics show that both proteins are significantly less stable than other amyloidogenic variants. However, despite a similar thermodynamic stability, L111M variant seems to have enhanced susceptibility to cleavage and a lower tendency to form fibrils than S52P in the presence of specific proteases and biomechanical forces. Heparin strongly enhances the fibrillogenic capacity of L111M transthyretin, but has no effect on the S52P variant. Fibrillar seeds similarly affect the fibrillogenesis of both proteins, with a stronger effect on the L111M variant. According to our model of mechano-enzymatic fibrillogenesis, both full-length and truncated monomers, released after the first cleavage, can enter into fibrillogenesis or degradation pathways. Our findings show that the kinetics of the two processes can be affected by several factors, such as intrinsic amyloidogenicity due to the specific mutations, environmental factors including heparin and fibrillar seeds that significantly accelerate the fibrillogenic pathway.
| Type: | Article |
|---|---|
| Title: | Degradation versus fibrillogenesis, two alternative pathways modulated by seeds and glycosaminoglycans |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/pro.4931 |
| Publisher version: | http://dx.doi.org/10.1002/pro.4931 |
| Language: | English |
| Additional information: | © 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | amyloidosis, cardiac myopathy, fibrillogenesis, proteolysis, transthyretin, Humans, Glycosaminoglycans, Prealbumin, Amyloidosis, Amyloid, Heparin |
| 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/10188311 |
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