Key result
Cofilin-2 naturally self-assembles into amyloid-like structures and cross-seeds the aggregation of other proteins.
Why the study?
It remains unknown if cofilin-2 has an innate propensity to form amyloid-like structures and its potential role in myopathies.
Cofilin-2 possesses an intrinsic ability to form amyloid-like structures and promote the aggregation of other proteins, providing mechanistic insights into its potential role in myopathies and idiopathic dilated cardiomyopathy.
Cofilin-2 amyloid propensity is hypothesis-generating in cardiomyopathy; leaves open pathogenic or therapeutic relevance in patients.
Cofilin-2 is a member of the ADF/cofilin family, expressed extensively in adult muscle cells and involved in muscle maintenance and regeneration. Phosphorylated cofilin-2 is found in pre-fibrillar aggregates formed during idiopathic dilated cardiomyopathy. A recent study shows that phosphorylated cofilin-2, under oxidative distress, forms fibrillar aggregates. However, it remains unknown if cofilin-2 holds an innate propensity to form amyloid-like structures. In the present study, we employed various computational and biochemical techniques to explore the amyloid-forming potential of cofilin-2. We report that cofilin-2 possesses aggregation-prone regions (APRs), and these APRs get exposed to the surface, become solvent-accessible, and are involved in the intermolecular interactions during dimerization, an early stage of aggregation. Furthermore, the cofilin-2 amyloids, formed under physiological conditions, are capable of cross-seeding other monomeric globular proteins and amino acids, thus promoting their aggregation. We further show that Cys-39 and Cys-80 are critical in maintaining the thermodynamic stability of cofilin-2. The destabilizing effect of oxidation at Cys-39 but not that at Cys-80 is mitigated by Ser-3 phosphorylation. Cysteine oxidation leads to partial unfolding and loss of structure, suggesting that cysteine oxidation further induces early events of cofilin-2 aggregation. Overall, our results pose a possibility that cofilin-2 amyloidogenesis might be involved in the pathophysiology of diseases, such as myopathies. We propose that the exposure of APRs to the surface could provide mechanistic insight into the higher-order aggregation and amyloidogenesis of cofilin-2. Moreover, the cross-seeding activity of cofilin-2 amyloids hints towards its involvement in the hetero-aggregation in various amyloid-linked diseases.
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Kaushik et al. (2021) studied Myopathies. Cofilin-2 was evaluated on Amyloid-like structure formation and cross-seeding activity. Cofilin-2 possesses an innate propensity to self-assemble into amyloid-like structures under physiological conditions and can cross-seed the aggregation of other globular proteins and amino acids.
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