6owv

Crystal structure of a Human Cardiac Calsequestrin Filament

spinqualitylabelsall models 6owv, resolution 1.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6owv is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.88Å Ligands: CL, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CASQ2_HUMAN Defects in CASQ2 are the cause of catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) [MIM:611938; also known as stress-induced polymorphic ventricular tachycardia (VTSIP). CPVT2 is an autosomal recessive form of arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Function CASQ2_HUMAN Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. The release of calcium bound to calsequestrin through a calcium release channel triggers muscle contraction. The skeletal muscle isoform (CASQ1) binds around 80 Ca(2+) ions, while the cardiac isoform (CASQ2) binds approximately 60 Ca(2+) ions. Publication Abstract from PubMed 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. The structure of a calsequestrin filament reveals mechanisms of familial arrhythmia.,Titus EW, Deiter FH, Shi C, Wojciak J, Scheinman M, Jura N, Deo RC Nat Struct Mol Biol. 2020 Oct 12. pii: 10.1038/s41594-020-0510-9. doi:, 10.1038/s41594-020-0510-9. PMID:33046906 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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