Cofilins are small protein of the actin depolymerizing family. Actin polymerization/depolymerization is central to a number of critical cellular physiological tasks making cofilin a key protein for several physiological functions of the cell. Cofilin activity is mainly regulated by phosphorylation on serine residue 3 making this post-translational modification key to the regulation of myofilament integrity. In fact, in this form, the protein segregates in myocardial aggregates in human idiopathic dilated cardiomyopathy. Since myofilament network is an early target of oxidative stress we investigated the molecular changes induced by oxidation on cofilin isoforms and their interplay with the protein phosphorylation state to get insight on whether/how those changes may predispose to early protein aggregation. Using different and complementary approaches we characterized the aggregation properties of cofilin-2 and its phosphomimetic variant (S3D) in response to oxidative stress in silico, in vitro and on isolated cardiomyocytes. We found that the phosphorylated (inactive) form of cofilin-2 is mechanistically linked to the formation of an extended network of fibrillar structures induced by oxidative stress via the formation of a disulfide bond between Cys39 and Cys80. Such phosphorylation-dependent effect is likely controlled by changes in the hydrogen bonding network involving Cys39. We found that the sulfide ion inhibits the formation of such structures. This might represent the mechanism for the protective effect of the therapeutic agent Na2S on ischemic injury.

Phosphorylated cofilin-2 is more prone to oxidative modifications on Cys39 and favors amyloid fibril formation / Pignataro, M.; Di Rocco, G.; Lancellotti, L.; Bernini, F.; Subramanian, K.; Castellini, E.; Bortolotti, C. A.; Malferrari, D.; Moro, D.; Valdre, G.; Borsari, M.; Monte, F. D.. - In: REDOX BIOLOGY. - ISSN 2213-2317. - 37:(2020), pp. 1-11. [10.1016/j.redox.2020.101691]

Phosphorylated cofilin-2 is more prone to oxidative modifications on Cys39 and favors amyloid fibril formation

Pignataro M.;Di Rocco G.;Lancellotti L.;Bernini F.;Castellini E.;Bortolotti C. A.;Malferrari D.;Valdre G.;Borsari M.
;
2020-01-01

Abstract

Cofilins are small protein of the actin depolymerizing family. Actin polymerization/depolymerization is central to a number of critical cellular physiological tasks making cofilin a key protein for several physiological functions of the cell. Cofilin activity is mainly regulated by phosphorylation on serine residue 3 making this post-translational modification key to the regulation of myofilament integrity. In fact, in this form, the protein segregates in myocardial aggregates in human idiopathic dilated cardiomyopathy. Since myofilament network is an early target of oxidative stress we investigated the molecular changes induced by oxidation on cofilin isoforms and their interplay with the protein phosphorylation state to get insight on whether/how those changes may predispose to early protein aggregation. Using different and complementary approaches we characterized the aggregation properties of cofilin-2 and its phosphomimetic variant (S3D) in response to oxidative stress in silico, in vitro and on isolated cardiomyocytes. We found that the phosphorylated (inactive) form of cofilin-2 is mechanistically linked to the formation of an extended network of fibrillar structures induced by oxidative stress via the formation of a disulfide bond between Cys39 and Cys80. Such phosphorylation-dependent effect is likely controlled by changes in the hydrogen bonding network involving Cys39. We found that the sulfide ion inhibits the formation of such structures. This might represent the mechanism for the protective effect of the therapeutic agent Na2S on ischemic injury.
37
1
11
Phosphorylated cofilin-2 is more prone to oxidative modifications on Cys39 and favors amyloid fibril formation / Pignataro, M.; Di Rocco, G.; Lancellotti, L.; Bernini, F.; Subramanian, K.; Castellini, E.; Bortolotti, C. A.; Malferrari, D.; Moro, D.; Valdre, G.; Borsari, M.; Monte, F. D.. - In: REDOX BIOLOGY. - ISSN 2213-2317. - 37:(2020), pp. 1-11. [10.1016/j.redox.2020.101691]
Pignataro, M.; Di Rocco, G.; Lancellotti, L.; Bernini, F.; Subramanian, K.; Castellini, E.; Bortolotti, C. A.; Malferrari, D.; Moro, D.; Valdre, G.; Borsari, M.; Monte, F. D.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1210736
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