6OWV

Crystal structure of a Human Cardiac Calsequestrin Filament

6OWV の概要

• エントリーDOI: 10.2210/pdb6owv/pdb
• 関連するPDBエントリー: 6OWW
• 分子名称: Calsequestrin-2, SULFATE ION, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: calsequestrin, calcium-binding proteins, sarcoplasmic reticulum proteins, metal binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46047.09

構造登録者

Titus, E.W.,Deiter, F.H.,Shi, C.,Jura, N.,Deo, R.C. (登録日: 2019-05-12, 公開日: 2020-07-01, 最終更新日: 2023-10-11)

主引用文献

Titus, E.W.,Deiter, F.H.,Shi, C.,Wojciak, J.,Scheinman, M.,Jura, N.,Deo, R.C.
The structure of a calsequestrin filament reveals mechanisms of familial arrhythmia.
Nat.Struct.Mol.Biol., 27:1142-1151, 2020

PubMed Abstract: Mutations in the calcium-binding protein calsequestrin cause the highly lethal familial arrhythmia catecholaminergic polymorphic ventricular tachycardia (CPVT). In vivo, calsequestrin multimerizes into filaments, but there is not yet an atomic-resolution structure of a calsequestrin filament. We report a crystal structure of a human cardiac calsequestrin filament with supporting mutational analysis and in vitro filamentation assays. We identify and characterize a new disease-associated calsequestrin mutation, S173I, that is located at the filament-forming interface, and further show that a previously reported dominant disease mutation, K180R, maps to the same surface. Both mutations disrupt filamentation, suggesting that disease pathology is due to defects in multimer formation. An ytterbium-derivatized structure pinpoints multiple credible calcium sites at filament-forming interfaces, explaining the atomic basis of calsequestrin filamentation in the presence of calcium. Our study thus provides a unifying molecular mechanism through which dominant-acting calsequestrin mutations provoke lethal arrhythmias.

PubMed: 33046906
DOI: 10.1038/s41594-020-0510-9

実験手法

X-RAY DIFFRACTION (1.88 Å)