8P35

Mutant human titin immunoglobulin-like 21 domain - C3575S

8P35 の概要

• エントリーDOI: 10.2210/pdb8p35/pdb
• 関連するPDBエントリー: 8OVU
• 分子名称: Titin (2 entities in total)
• 機能のキーワード: titin, muscle, immunoglobulin-like, structural protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 64855.24

構造登録者

Martinez-Martin, I.,Crousilles, A.,Mortensen, S.A.,Alegre-Cebollada, J.,Wilmanns, M. (登録日: 2023-05-17, 公開日: 2023-11-29, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)