The biochemically defined super relaxed state of myosin—A paradox

Mohran, Saffie; Kooiker, Kristina; Mahoney-Schaefer, Max; Mandrycky, Christian; Kao, Kerry; Tu, An-Yue; Freeman, Jeremy; Moussavi-Harami, Farid; Geeves, Michael; Regnier, Michael

doi:10.1016/j.jbc.2023.105565

Journal of Biological Chemistry

2024

DOI: 10.1016/j.jbc.2023.105565

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The biochemically defined super relaxed state of myosin—A paradox

Saffie Mohran,

Kristina Kooiker,

Max Mahoney-Schaefer

et al.

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2024

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Cited by 8 publications

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Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation

Liang,

Kazmierczak,

Veerasammy

et al. 2024

Cytoskeleton

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We investigated the impact of the phosphomimetic (Ser15 → Asp15) myosin regulatory light chain (S15D‐RLC) on the Super‐Relaxed (SRX) state of myosin using previously characterized transgenic (Tg) S15D‐D166V rescue mice, comparing them to the Hypertrophic Cardiomyopathy (HCM) Tg‐D166V model and wild‐type (WT) RLC mice. In the Tg‐D166V model, we observed a disruption of the SRX state, resulting in a transition from SRX to DRX (Disordered Relaxed) state, which explains the hypercontractility of D166V‐mutated myosin motors. The presence of the S15D moiety in Tg‐S15D‐D166V mice restored the SRX/DRX balance to levels comparable to Tg‐WT, thus mitigating the hypercontractile behavior associated with the HCM‐D166V mutation. Additionally, we investigated the impact of delivering the S15D‐RLC molecule to the hearts of Tg‐D166V mice via adeno‐associated virus (AAV9) and compared their condition to AAV9‐empty vector‐injected or non‐injected Tg‐D166V animals. Tg‐D166V mice injected with AAV9 S15D‐RLC exhibited a significantly higher proportion of myosin heads in the SRX state compared to those injected with AAV9 empty vector or left non‐injected. No significant effect was observed in Tg‐WT hearts treated similarly. These findings suggest that AAV9‐delivered phosphomimetic S15D‐RLC modality mitigates the abnormal Tg‐D166V phenotype without impacting the normal function of Tg‐WT hearts. Global longitudinal strain analysis supported these observations, indicating that the S15D moiety can alleviate the HCM‐D166V phenotype by restoring SRX stability and the SRX ↔ DRX equilibrium.

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Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation

Liang,

Kazmierczak,

Veerasammy

et al. 2024

Cytoskeleton

View full text Add to dashboard Cite

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Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy

Sitbon,

Kazmierczak,

Liang

et al. 2024

iScience

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Functional control of myosin motors in the cardiac cycle

Irving

2024

Nat Rev Cardiol

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The biochemically defined super relaxed state of myosin—A paradox

Cited by 8 publications

References 51 publications

Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation

Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation

Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy

Functional control of myosin motors in the cardiac cycle

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