S165F mutation-induced Junctophilin-2 autoinhibition impairs Ca²⁺ signaling in hypertrophic cardiomyopathy.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder often linked to mutations in various genes, including junctophilin-2 (JPH2), a key non-sarcomeric protein essential for forming junctional membrane complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR). Deciphering the molecular mechanisms behind these mutations is crucial for the development of effective therapies. In this study, we investigate the pathological effects of the HCM-associated S165F mutation in JPH2. Through integrated structural and biochemical analyses, we demonstrate that the S165F mutation induces an unintended intramolecular interaction in JPH2, disrupting its normal interaction with CaV1.2. This mutation compromises ER-PM junctions and disrupts Ca²⁺ s

SUBMITTER: Li Z 

PROVIDER: S-EPMC12748787 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature