Assembly of human ATP synthase

我们摄入的食物中的能量被我们体内的氧化过程分解。净效应是以跨越线粒体内膜的电压的形式产生势能。线粒体是细胞的动力库，它产生所需的燃料，为肌肉活动、思维过程以及复制DNA和蛋白质等生物过程提供能量。燃料是以三磷酸腺苷分子的形式提供的，简称为ATP。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。线粒体中的三磷酸腺苷是由数百万个拷贝的微小分子机器通过被称为三磷酸腺苷合成酶的旋转作用产生的。线粒体被两层生物膜包围，三磷酸腺苷合成酶嵌入内部，其合成的头部指向内部，使它们看起来像微小的蘑菇。在ATP合成酶的膜嵌入区，跨膜的电压使转子以每秒约100-200转的速度转动。转子附着在一个坚固的茎上，茎穿入催化头，茎的旋转重组乏燃料元素形成新的ATP，并释放到线粒体中。头部和静态结构由称为外周茎的第二个蛋白质连接，这是防止头部和转子一起转动所必需的。从线粒体，三磷酸腺苷通过运输过程分布在细胞周围，在三磷酸腺苷释放能量后，以二磷酸腺苷(ADP)和无机磷分子的形式将乏燃料带回线粒体，重新组合成新的三磷酸腺苷分子。旋转机械既复杂又脆弱。它们需要在线粒体形成时被组装在一起，并在它们分解时被替换。它们由18种不同种类的29种蛋白质组成。除了两个以外，所有这些蛋白质的制造指令都位于细胞核中，这些蛋白质在线粒体外制造，然后输入到内部。在这里，它们与线粒体内的另外两种蛋白质一起组装成ATP合成酶，线粒体中的指令来自那里的一个小DNA分子。我们正在研究这些复杂的机器是如何组装的。我们发现，蛋白质首先被组装成特定的预制模块，然后连接在一起构成完整的机器，就像汽车的更简单的部件在制造完整的汽车之前被组装到发动机、变速箱和其他模块中一样。ATP合成酶模块对应于催化头、转子的膜部和外周茎。转子的膜部分和催化头的组装需要其他不是成品机器一部分的蛋白质来帮助组装过程。我们正在研究这些因素的特性，部分原因是人类至少在其中两个因素上发生突变会导致疾病。最后，完成的机器配对，在它们的膜域中连接在一起，头部彼此之间大约成90度，这些对关联成长列，帮助赋予线粒体内膜其特有的内陷外观。我们想更多地了解这是如何发生的。

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.