Assembly of human ATP synthase

我们摄入的食物中的能量会通过体内的氧化过程被分解。净效应是以电压的形式在线粒体的内膜上产生势能。线粒体是细胞的发电厂，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。这种燃料以三磷酸腺苷分子的形式提供，简称ATP。每天，我们每个人在细胞的线粒体中产生50-60公斤的ATP来维持我们的身体活动。ATP是由一个微小的分子机器在线粒体中通过旋转作用产生的，这个机器被称为ATP合酶。线粒体被两层生物膜包围，ATP合酶嵌入其中一层，它们的合成头指向里面，使它们看起来像小蘑菇。在ATP合酶的膜嵌入区，穿过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杆上，杆穿过催化头，杆的旋转重组了乏燃料元素，形成新的ATP，释放到线粒体中。头部和静态结构由另一种称为外周柄的蛋白质连接，这是防止头部和转子一起转动所必需的。从线粒体，ATP通过运输过程分布在细胞周围，在ATP释放能量后，以二磷酸腺苷（ADP）和无机磷酸盐分子形式的乏燃料被带回线粒体重新组合成新的ATP分子。旋转机器既复杂又脆弱。当线粒体形成时，它们需要组合在一起，当它们分解时，它们需要被替换。它们由18种不同的29种蛋白质组成。除了两种蛋白质外，制造这些蛋白质的指令都存在于细胞核中，这些蛋白质在线粒体外制造，然后输入到线粒体内。在这里，它们与另外两种蛋白质一起被组装成ATP合成酶，这两种蛋白质是在线粒体内根据一个小DNA分子的指令合成的。我们正在研究这些复杂的机器是如何组装起来的。我们发现，这些蛋白质首先被组装成特定的预制模块，然后连接在一起组成完整的机器，就像汽车的简单部件在组装成整车之前被组装成发动机、变速箱和其他模块一样。ATP合成酶模块对应于催化头，转子的膜部分和外围杆。转子的膜部分和催化头的组装需要其他蛋白质，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种因素的人类突变会导致疾病。最后，完成的机器配对，在它们的膜域连接在一起，头部彼此成90度，成对成对地形成长排，帮助线粒体的内陷膜呈现出它们特有的外观。我们想知道这是如何发生的。

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.