Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy

Martínez-Martín, Inés; Crousilles, Audrey; Ochoa, Juan Pablo; Velázquez-Carreras, Diana; Mortensen, Simon A.; Herrero-Galán, Elías; Delgado Blanco, Javier; Domínguez, Fernando; García-Pavía, Pablo; Sancho, David de; Wilmanns, Matthias; Alegre-Cebollada, Jorge

doi:http://dx.doi.org/10.1016/j.celrep.2023.113490

Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy

Llicència

Citació

Martinez-Martin I, Crousilles A, Ochoa JP, Velazquez-Carreras D, Mortensen SA, Herrero-Galan E, Delgado J, Dominguez F, Garcia-Pavia P, de Sancho D, Wilmanns M, Alegre-Cebollada J. Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy. Cell Rep. 2023 Dec 26;42(12):113490. DOI: 10.1016/j.celrep.2023.113490

Resum

The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.