5JDE

Crystal structure of I9-I11 tandem from titin (P1)

5JDE の概要

• エントリーDOI: 10.2210/pdb5jde/pdb
• 分子名称: Titin (2 entities in total)
• 機能のキーワード: titin, structural protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q8WZ42
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59410.43

構造登録者

Williams, R.,Bogomolovas, J.,Labiet, S.,Mayans, O. (登録日: 2016-04-16, 公開日: 2016-09-14, 最終更新日: 2024-01-10)

主引用文献

Bogomolovas, J.,Fleming, J.R.,Anderson, B.R.,Williams, R.,Lange, S.,Simon, B.,Khan, M.M.,Rudolf, R.,Franke, B.,Bullard, B.,Rigden, D.J.,Granzier, H.,Labeit, S.,Mayans, O.
Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I.
Open Biology, 6:-, 2016

PubMed Abstract: Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.

PubMed: 27683155
DOI: 10.1098/rsob.160114

実験手法

X-RAY DIFFRACTION (1.9 Å)