5VSN

Crystal structure of mouse ryanodine receptor 2 SPRY2 domain (1080-1253) disease mutant P1124L

Summary for 5VSN

• Entry DOI: 10.2210/pdb5vsn/pdb
• Descriptor: Ryanodine receptor 2, GLYCEROL, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: ryanodine receptor, disease mutant, transport protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 19295.73

Authors

Yuchi, Z.,Van Petegem, F. (deposition date: 2017-05-12, release date: 2018-05-23, Last modification date: 2023-10-04)

Primary citation

Alvarado, F.J.,Bos, J.M.,Yuchi, Z.,Valdivia, C.R.,Hernandez, J.J.,Zhao, Y.T.,Henderlong, D.S.,Chen, Y.,Booher, T.R.,Marcou, C.A.,Van Petegem, F.,Ackerman, M.J.,Valdivia, H.H.
Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2.
JCI Insight, 5:-, 2019

PubMed Abstract: Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a novel mutation in the ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca2+], indicating a luminal gain-of-function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 yr of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 mo of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally-divergent behavior triggers arrhythmias and structural cardiac remodeling, and involves overexpression of calmodulin as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

PubMed: 30835254
DOI: 10.1172/jci.insight.126544

Experimental method

X-RAY DIFFRACTION (1.439 Å)