6WOU

Cryo-EM structure of recombinant mouse Ryanodine Receptor type 2 mutant R176Q in complex with FKBP12.6 in nanodisc

This is a non-PDB format compatible entry.

Summary for 6WOU

• Entry DOI: 10.2210/pdb6wou/pdb
• EMDB information: 21860 21861 21862
• Descriptor: Ryanodine receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1B, ZINC ION (3 entities in total)
• Functional Keywords: ryanodine receptor, calcium channel, mutation, ntda mutation, ryr2, polymorphic catecholergic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, transport protein-isomerase complex, transport protein/isomerase
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 8
• Total formula weight: 2308958.86

Authors

Iyer, K.A.,Hu, Y.,Kurebayashi, N.,Murayama, T.,Samso, M. (deposition date: 2020-04-25, release date: 2020-08-05, Last modification date: 2024-05-29)

Primary citation

Iyer, K.A.,Hu, Y.,Nayak, A.R.,Kurebayashi, N.,Murayama, T.,Samso, M.
Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM.
Sci Adv, 6:eabb2964-eabb2964, 2020

PubMed Abstract: Mutations in ryanodine receptors (RyRs), intracellular Ca channels, are associated with deadly disorders. Despite abundant functional studies, the molecular mechanism of RyR malfunction remains elusive. We studied two single-point mutations at an equivalent site in the skeletal (RyR1 R164C) and cardiac (RyR2 R176Q) isoforms using ryanodine binding, Ca imaging, and cryo-electron microscopy (cryo-EM) of the full-length protein. Loss of the positive charge had greater effect on the skeletal isoform, mediated via distortion of a salt bridge network, a molecular latch inducing rotation of a cytoplasmic domain, and partial progression to open-state traits of the large cytoplasmic assembly accompanied by alteration of the Ca binding site, which concur with the major "hyperactive" feature of the mutated channel. Our cryo-EM studies demonstrated the allosteric effect of a mutation situated ~85 Å away from the pore and identified an isoform-specific structural effect.

PubMed: 32832689
DOI: 10.1126/sciadv.abb2964

Experimental method

ELECTRON MICROSCOPY (3.27 Å)