6OWV
Crystal structure of a Human Cardiac Calsequestrin Filament
Summary for 6OWV
| Entry DOI | 10.2210/pdb6owv/pdb |
| Related | 6OWW |
| Descriptor | Calsequestrin-2, SULFATE ION, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | calsequestrin, calcium-binding proteins, sarcoplasmic reticulum proteins, metal binding protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46047.09 |
| Authors | Titus, E.W.,Deiter, F.H.,Shi, C.,Jura, N.,Deo, R.C. (deposition date: 2019-05-12, release date: 2020-07-01, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 33046906DOI: 10.1038/s41594-020-0510-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.88 Å) |
Structure validation
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