<br>从“黑匣子”到“多米诺骨牌效应”机制：我们从呼吸复合体I的结构中学到了什么,Biochemical Journal

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从“黑匣子”到“多米诺骨牌效应”机制：我们从呼吸复合体I的结构中学到了什么
Biochemical Journal ( IF 4.4 ) Pub Date : 2023-03-15 , DOI: 10.1042/bcj20210285
Leonid A Sazanov ₁

Affiliation

我和我的团队从 1994 年开始研究呼吸复合体 I 已近 30 年，当时它被称为生物能学的 L 形巨型“黑匣子”。第一个突破是外围臂的 X 射线结构，然后是膜臂的结构，最后是嗜热栖热菌的整个复合体。冷冻电镜技术的发展使我们能够在 2016 年首次解析出两倍大、∼1 MDa 的哺乳动物酶的完整结构。然而，长距离耦合的机制是两个电子的转移与四个质子的泵浦。膜仍然是一个谜。最近，我们在一系列氧化还原条件（包括催化转换）下解析了哺乳动物和细菌复合物 I 的高分辨率结构。这使我们能够为复合物 I 和相关蛋白质家族提出一种稳健且通用的机制。氧化还原反应最初驱动醌腔周围的构象变化和底物质子的长距离转移。这些为沿着膜臂的一系列静电驱动的质子转移（“多米诺骨牌效应”）建立了一个阶段，最终导致质子从远端反向转运蛋白样亚基中排出。该机制与之前的建议截然不同，然而，它自然地解释了复合物 I 的所有不寻常的结构特征。在这篇综述中，我讨论了复合物 I 的知识状况，包括当前最具争议的问题。

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From the ‘black box' to ‘domino effect' mechanism: what have we learned from the structures of respiratory complex I

My group and myself have studied respiratory complex I for almost 30 years, starting in 1994 when it was known as a L-shaped giant ‘black box' of bioenergetics. First breakthrough was the X-ray structure of the peripheral arm, followed by structures of the membrane arm and finally the entire complex from Thermus thermophilus. The developments in cryo-EM technology allowed us to solve the first complete structure of the twice larger, ∼1 MDa mammalian enzyme in 2016. However, the mechanism coupling, over large distances, the transfer of two electrons to pumping of four protons across the membrane remained an enigma. Recently we have solved high-resolution structures of mammalian and bacterial complex I under a range of redox conditions, including catalytic turnover. This allowed us to propose a robust and universal mechanism for complex I and related protein families. Redox reactions initially drive conformational changes around the quinone cavity and a long-distance transfer of substrate protons. These set up a stage for a series of electrostatically driven proton transfers along the membrane arm (‘domino effect'), eventually resulting in proton expulsion from the distal antiporter-like subunit. The mechanism radically differs from previous suggestions, however, it naturally explains all the unusual structural features of complex I. In this review I discuss the state of knowledge on complex I, including the current most controversial issues.

更新日期：2023-03-16

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