Background: L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown. Methods: The effect of Hcy on the conformational properties of wt- and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia. Results: We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species. Conclusions: Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters. General significance: Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation.
Leri, M., Rebuzzini, P., Caselli, A., Luti, S., Natalello, A., Giorgetti, S., et al. (2020). S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1864(1) [10.1016/j.bbagen.2019.129453].
|Citazione:||Leri, M., Rebuzzini, P., Caselli, A., Luti, S., Natalello, A., Giorgetti, S., et al. (2020). S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1864(1) [10.1016/j.bbagen.2019.129453].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||No|
|Titolo:||S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset|
|Autori:||Leri, M; Rebuzzini, P; Caselli, A; Luti, S; Natalello, A; Giorgetti, S; Marchese, L; Garagna, S; Stefani, M; Paoli, P; Bucciantini, M|
NATALELLO, ANTONINO [Membro del Collaboration Group]
|Data di pubblicazione:||2020|
|Rivista:||BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bbagen.2019.129453|
|Appare nelle tipologie:||01 - Articolo su rivista|