Assembly of human ATP synthase

人 ATP 合酶的组装

• 批准号: MR/V009672/1
• 负责人: John Walker
• 金额: $ 107.24万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009672%2F1
• 关键词: Assembly; human; ATP; synthase

Energy from the food we ingest is broken down by oxidative processes in our bodies. The net effect is to generate potential energy in the form of a voltage across the inner membranes of the mitochondria. The mitochondria are the cellular power-houses that generate the fuel required to provide the energy for biological processes such as muscular action, thought processes and replicating DNA and proteins. The fuel is provided in the form of the molecule adenosine triphosphate, known simply as ATP. Every day, each one of us generates 50-60 kg of ATP in the mitochondria of our cells to sustain our bodily activities. The ATP is produced in the mitochondria by millions of copies of a tiny molecular machine with a rotary action known as ATP synthase. The mitochondria are surrounded by two biological membranes and the ATP synthases are embedded in the inner one, with their synthetic heads pointing towards the inside making them resemble tiny mushrooms. In the membrane embedded region of the ATP synthase, the voltage across the membrane makes a rotor turn at about 100-200 rotations every second. The rotor is attached to a robust stalk which penetrates into the catalytic head, and the rotation of the stalk recombines spent fuel elements to form new ATP which is released into the mitochondria. The head and a static structure are joined by a second protein linkage called the peripheral stalk, which is required to prevent the head and rotor turning together. From the mitochondrion, the ATP is distributed around the cell by transport processes and, after release of energy from ATP, the spent fuel in the form of the molecules adenosine diphosphate (ADP) and inorganic phosphate is brought back to the mitochondria to be recombined into new ATP molecules. The rotary machines are both complex and fragile. They need to be put together when the mitochondria are made, and replaced when they break down. They are made from 29 proteins of 18 different kinds. The instructions for making all but two of these proteins resides in the cellular nucleus, and these proteins are made outside the mitochondrion and then imported to the inside. Here they are assembled into the ATP synthases together with the two other proteins that are made inside the mitochondrion with instructions from a small DNA molecule that resides there. We are studying how these complicated machines are assembled. We have discovered that the proteins are first assembled into specific preformed modules and then joined together to make the complete machine, rather like the simpler components of a car are assembled into the engine, gear-box and other modules before being made into the complete vehicle. The ATP synthase modules correspond to the catalytic head, the membrane part of the rotor and the peripheral stalk. The assembly of the membrane part of the rotor and that catalytic head require other proteins that are not part of the finished machines to help in the assembly process. We are studying the properties of these factors, partly because human mutations in at least two of them leads to disease. Finally, the completed machines pair up, linked together in their membrane domains, with the heads at about 90 degrees to each other, and the pairs associate into long rows and help give the inner membranes of the mitochondria their characteristic invaginated appearance. We want to know more about how this happens.

我们摄入的食物的能量被体内的氧化过程分解。净效应是在线粒体内部膜上以电压形式产生势能。线粒体是细胞动力室，可产生为生物学过程提供能量（例如肌肉作用，思维过程和复制DNA和蛋白质）所需的燃料。燃料以三磷酸分子腺苷的形式（仅称为ATP）提供。每天，我们每个人都会在细胞的线粒体中产生50-60公斤的ATP，以维持我们的身体活动。 ATP在线粒体中由数百万个微小的分子机拷贝产生，其旋转作用称为ATP合酶。线粒体被两个生物膜包围，ATP合酶嵌入内部，其合成头指向内部，使它们类似于微小的蘑菇。在ATP合酶的膜嵌入区域中，整个膜的电压每秒以大约100-200旋转的旋转方式转动。转子连接到渗透到催化头部的强大茎上，茎重组的旋转花费了燃料元素，以形成新的ATP，该ATP被释放到线粒体中。头部和静态结构与第二个称为外围茎的第二个蛋白质连接在一起，该蛋白质连接是防止头和转子一起转动所必需的。从线粒体中，ATP通过传输过程分布在细胞周围，在ATP释放能量后，以分子腺苷二磷酸（ADP）形式的耗尽燃料和无机磷酸盐的形式被带回线粒体，将其重新组合为新的ATP分子。旋转机既复杂又脆弱。将线粒体制成时，需要将它们放在一起，并在分解时更换。它们是由18种不同种类的29种蛋白质制成的。除这些蛋白质中的所有两个以外的所有指令都存在于细胞核中，并且这些蛋白质是在线粒体外制成的，然后进口到内部。在这里，它们与其他两种蛋白质一起组装到ATP合成酶中，这些蛋白质与线粒体内部产生的蛋白质以及驻留在那里的小DNA分子的指令。我们正在研究这些复杂的机器是如何组装的。我们已经发现，首先将蛋白质组装成特定的预先形成的模块，然后将其连接在一起制成完整的机器，就像将汽车的较简单组件组装到发动机，齿轮盒和其他模块中之前，然后将其组装到完整的车辆中。 ATP合酶模块对应于催化头，转子的膜部分和外围茎。转子的膜部分的组装和催化头需要其他蛋白质，这些蛋白质不是成品机器的一部分，以帮助组装过程。我们正在研究这些因素的特性，部分原因是其中至少两个的人类突变导致疾病。最后，完整的机器配对，将其在其膜域中连接在一起，头部约为90度，彼此之间的头部彼此相连，并且成对成长为长排，并有助于使线粒体的内部膜具有特征性的内脏外观。我们想进一步了解这种情况。