Electron Transfer Coupled to Conformational Dynamics in Cell Respiration.
Electron Transfer Coupled to Conformational Dynamics in Cell Respiration.
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DOI：
10.3389/fmolb.2021.711436
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发表时间：
2021
影响因子：
5
通讯作者：
Sharma V
中科院分区：
文献类型：
--
作者：
Reidelbach M;Zimmer C;Meunier B;Rich PR;Sharma V
细胞呼吸是许多生物体产生能量所必需的基本过程。线粒体和许多细菌呼吸链中的末端电子传递复合体是细胞色素C氧化酶(CcO)。这将细胞色素c/氧氧化还原反应中释放的能量转化为跨膜质子电化学梯度，随后用于为ATP合成提供动力。尽管对电子和质子转移路径有详细的了解，但一个核心问题仍然是哺乳动物线粒体形式的CcO中电子和质子转移之间的耦合在机械上是否与细菌的对应。在这里，我们关注的是I亚基跨膜螺旋(TMH)X的H376和G384之间的保守跨度。这一构象动力学截面被认为是哺乳动物CcO中氧化还原活性与质子转移的H途径之间的联系。两个螺旋X突变体Val380Met(V380M)和Gly384Asp(G384D)产生于遗传易感的酵母CcO中，通过抑制蛋白内电子传递和CcO周转而导致呼吸缺陷表型。通过对野生型和突变型牛和酵母CCOS进行长时间尺度原子分子动力学模拟，研究了这些变体的分子方面。我们在牛和酵母的CCOS的TMH X的这个跨度中发现了依赖于氧化还原和突变状态的构象变化，这有力地表明这个动态模块在优化蛋白质内电子传递方面发挥了关键作用。
Cellular respiration is a fundamental process required for energy production in many organisms. The terminal electron transfer complex in mitochondrial and many bacterial respiratory chains is cytochrome c oxidase (CcO). This converts the energy released in the cytochrome c/oxygen redox reaction into a transmembrane proton electrochemical gradient that is used subsequently to power ATP synthesis. Despite detailed knowledge of electron and proton transfer paths, a central question remains as to whether the coupling between electron and proton transfer in mammalian mitochondrial forms of CcO is mechanistically equivalent to its bacterial counterparts. Here, we focus on the conserved span between H376 and G384 of transmembrane helix (TMH) X of subunit I. This conformationally-dynamic section has been suggested to link the redox activity with the putative H pathway of proton transfer in mammalian CcO. The two helix X mutants, Val380Met (V380M) and Gly384Asp (G384D), generated in the genetically-tractable yeast CcO, resulted in a respiratory-deficient phenotype caused by the inhibition of intra-protein electron transfer and CcO turnover. Molecular aspects of these variants were studied by long timescale atomistic molecular dynamics simulations performed on wild-type and mutant bovine and yeast CcOs. We identified redox- and mutation-state dependent conformational changes in this span of TMH X of bovine and yeast CcOs which strongly suggests that this dynamic module plays a key role in optimizing intra-protein electron transfers.