6J6L

Crystal structure of mouse Ryanodine Receptor 2 SPRY1 Domain (650-844) disease mutant I784F

Summary for 6J6L

• Entry DOI: 10.2210/pdb6j6l/pdb
• Descriptor: Ryanodine receptor 2, ISOPROPYL ALCOHOL (3 entities in total)
• Functional Keywords: ryanodine receptor 2, spry1, disease mutation, metal transport
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 44457.97

Authors

Ma, R.,Lin, L.,Yuchi, Z. (deposition date: 2019-01-15, release date: 2020-01-15, Last modification date: 2023-11-22)

Primary citation

Touat-Hamici, Z.,Blancard, M.,Ma, R.,Lin, L.,Iddir, Y.,Denjoy, I.,Leenhardt, A.,Yuchi, Z.,Guicheney, P.
A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.
Sci Rep, 11:5243-5243, 2021

PubMed Abstract: Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca release in response to cytosolic Ca was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.

PubMed: 33664309
DOI: 10.1038/s41598-021-84373-9

Experimental method

X-RAY DIFFRACTION (1.452 Å)