8P35

Mutant human titin immunoglobulin-like 21 domain - C3575S

Summary for 8P35

• Entry DOI: 10.2210/pdb8p35/pdb
• Related: 8OVU
• Descriptor: Titin (2 entities in total)
• Functional Keywords: titin, muscle, immunoglobulin-like, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 64855.24

Authors

Martinez-Martin, I.,Crousilles, A.,Mortensen, S.A.,Alegre-Cebollada, J.,Wilmanns, M. (deposition date: 2023-05-17, release date: 2023-11-29, Last modification date: 2024-01-10)

Primary citation

Martinez-Martin, I.,Crousilles, A.,Ochoa, J.P.,Velazquez-Carreras, D.,Mortensen, S.A.,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, 42:113490-113490, 2023

PubMed Abstract: 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.

PubMed: 38052212
DOI: 10.1016/j.celrep.2023.113490

Experimental method

X-RAY DIFFRACTION (2.2 Å)