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胆固醇通过Patched1运输的能量和离子合
T Bertie Ansell1, Robin A Corey1,2, Lucrezia Vittoria Viti3
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Science advances
|August 23, 2023
概括
补丁1 (PTCH1) 蛋白通过控制胆固醇运输来调节对的信号传递. 分子模拟揭示了胆固醇出口的离子合机制,澄清了PTCH1的存在.
科学领域:
- 分子生物学分子生物学
- 生物物理学的生物物理.
- 生物化学 生物化学
背景情况:
- 补丁1 (PTCH1) 是刺 (HH) 信号通路中的瘤抑制剂,对发育和组织维护至关重要.
- PTCH1对Smoothened (SMO) 的抑制与状胆固醇调节有关,尽管确切的机制尚不清楚.
研究的目的:
- 阐明中介于PTCH1.1的胆固醇运输的分子机制和能量.
- 调查离子合在PTCH1-介导胆固醇出口中的作用.
主要方法:
- 广泛的分子动力学 (MD) 模拟和自由能量计算,以通过PTCH1.1.进行胆固醇运输模型.
- 在体内使用PTCH1突变体进行的生物化学测定,以关联离子结合,跨膜运动和蛋白质活性.
- 对Dispatched1进行补充的MD模拟,以分析形态状态转换.
主要成果:
- 通过PTCH1.1,确定了15-20kJ/mol的能量屏障,用于通过PTCH1.1输出胆固醇.
- 发现1-3 Na+或2-3 K+离子的合有助于胆固醇的出口.
- 描述了PTCH1的不同运输状态,在Dispatched1.1中观察到Na+诱导的过渡.
结论:
- 这项研究提供了PTCH1运输状态及其过渡的第一个分子描述.
- 对于PTCH1-介导的胆固醇出口的离子静电测量得到了阐明,揭示了1-3 Na+或2-3 K+的参与.
- 研究结果提供了对控制PTCH1功能的能量和离子合机制的见解.
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