在1型氨酸受体离子通道中,EF手域和S2-S3循环之间的结构和功能相互作用
Venkat R Chirasani1, Millar Elferdink2, MacKenzie Kral2
1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; R.L. Juliano Structural Bioinformatics Core, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
The Journal of biological chemistry
|December 30, 2023
概括
分子动力学模拟揭示了骨肌肉里亚诺丁受体 (RyR) 的关键相互作用1. 这些发现突出了EF手-S2-S3循环相互作用的特点.
科学领域:
- 生物化学和分子生物学.
- 结构生物学是结构生物学.
- 生理学 生理学 生理学
背景情况:
- 骨肌肉的Ca2+释放通道,氨酸受体 (RyR) 1,对于肌肉收缩至关重要.
- 以前的研究表明,RyR1的EF手域和S2-S3循环之间存在调节相互作用,但细节尚不清楚.
研究的目的:
- 为了阐明RyR1.1.的EF手和S2-S3循环之间的分子相互作用.
- 研究这些相互作用对RyR1活动的功能后果.
主要方法:
- 分子动力学模拟以确定键相互作用.
- RyR1互补DNA的局部定向突变发生.
- HEK293细胞表达和 [3H]氨酸结合试验.
- 在基基因突变发生分析.
主要成果:
- 确定了关键的键:K4101 (EF手) -D4730 (S2-S3循环) 和EF手残留物 (E4075,Q4078,D4079) -R4736 (S2-S3循环).
- 在EF手中的K4101E/M突变降低了Ca2+/Mg2+抑制亲和力;K4101E增加了Ca2+激活亲和力.
- S2-S3循环突变D4730K/N没有显著改变抑制亲缘关系.
结论:
- EF手-S2-S3循环相互作用对RyR1.1.的Ca2+/Mg2+依赖性抑制至关重要.
- 这些发现为针对RyR1域相互作用的骨肌病症的潜在治疗策略提供了洞察力.
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