Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition
Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition
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DOI：
10.15252/embr.201643354
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发表时间：
2017-07-01
期刊：
影响因子：
7.7
通讯作者：
Bernardi, Paolo
中科院分区：
文献类型：
--
作者：
Giorgio, Valentina;Burchell, Victoria;Bernardi, Paolo
F-ATP脱氢酶将H+梯度的电化学能转化为ATP的化学能，具有显著的效率。线粒体F-ATP酶还可以经历Ca 2+依赖性转化以形成具有与渗透性转换孔（PTP）（细胞死亡中的关键参与者）相匹配的特性的通道。Ca 2+结合位点和Ca 2+可以将能量保存酶转化为促进细胞死亡的耗散结构的机制仍然未知。通过体外、体内和计算机模拟研究，我们（i）将PTP的“Ca 2+触发位点”精确定位到F-ATP合酶β亚基的催化位点，（ii）定义了从催化位点通过OSCP和侧柄传播到内膜的构象变化。β亚基的T163 S突变体，其显示出Ca 2 +-ATP水解的选择性降低，赋予对细胞和发育中的斑马鱼胚胎中的Ca 2+诱导的PTP依赖性死亡的抗性。这些发现是FATP合酶向通道转变的分子定义及其在细胞死亡中的作用的重大进展。
F-ATP synthases convert the electrochemical energy of the H+ gradient into the chemical energy of ATP with remarkable efficiency. Mitochondrial F-ATP synthases can also undergo a Ca2+-dependent transformation to form channels with properties matching those of the permeability transition pore (PTP), a key player in cell death. The Ca2+ binding site and the mechanism(s) through which Ca2+ can transform the energy-conserving enzyme into a dissipative structure promoting cell death remain unknown. Through in vitro, in vivo and in silico studies we (i) pinpoint the "Ca2+-trigger site" of the PTP to the catalytic site of the F-ATP synthase beta subunit and (ii) define a conformational change that propagates from the catalytic site through OSCP and the lateral stalk to the inner membrane. T163S mutants of the beta subunit, which show a selective decrease in Ca2+-ATP hydrolysis, confer resistance to Ca2+-induced, PTP-dependent death in cells and developing zebrafish embryos. These findings are a major advance in the molecular definition of the transition of FATP synthase to a channel and of its role in cell death.