Translocase of the Outer Mitochondrial Membrane: X-ray Structure Determination of Core Components

这项研究将解决蛋白质转运到线粒体的问题，线粒体是由复杂的双膜系统包围的细胞器，主要负责为主动呼吸细胞提供能量需求。每个线粒体周围的外膜或包膜通过膜间空间与第二层（或内层）膜分开。线粒体外膜转座酶（TOM）与线粒体内膜转座酶（TIM）协同介导未折叠的前蛋白进入线粒体。蛋白质在活跃折叠状态下通常体积庞大，因此前蛋白以延伸多肽链的形式通过膜，因为它们通过的通道相对狭窄。辅助蛋白有助于前蛋白的识别和靶向，并帮助它们在通过孔转运之前保持未折叠状态，然后确保它们一旦到达线粒体就能够折叠成正确的构象。我们的研究将需要确定TOM机器中选定成分的三维原子水平结构，使我们能够在分子细节中可视化蛋白质易位某些方面的定格快照。结合最近的生化数据，这些信息将提供一个架构框架，我们可以用它来帮助我们解释TOM成分和其他蛋白质之间复杂的结构-功能关系，它们在易位事件中整合它们的活动。最终，这样的基础研究将导致治疗人类线粒体缺陷相关疾病的策略的发展，其中包括帕金森病和阿尔茨海默病。

This research will address the issue of protein transport into mitochondria, cellular organelles bounded by a complex double-membrane system that are primarily responsible for servicing the energy requirements of actively respiring cells. The outer membrane, or envelope, surrounding each mitrochondrion, is separated from a second (or inner) membrane by an inter-membrane space. The translocase of the outer mitochondrial membrane (TOM) cooperates with the translocase of the inner mitochondrial membrane (TIM) to mediate the passage of unfolded preproteins into the mitochondria. Proteins are usually bulky in their active folded state, so preproteins transit the membrane as extended polypeptide chains, as the channel through which they pass is relatively narrow. Ancillary praoteins aid in recognition and targeting of preproteins, and help to maintain them in an unfolded state prior to their translocation through the pore, and later ensure that they are able to fold into the correct conformation once they have arrived in the mitochondria. Our research will entail determination of the three-dimensional atomic-level structures of selected constituents of the TOM machinery, allowing us to visualise freeze-frame snapshots of some aspects of protein translocation in molecular details. In combination with recent biochemical data, this information will provide an architectural framework which we can use to help in our interpretation of complicated structure-function relationships between components of TOM and other proteins with which they integrate their activities during translocation events. Ultimately such fundamental research will lead to the development of strategies for dealing with disorders linked to mitochondrial defects in humans, including, amongst others, Parkinson's and Alzheimer's diseases.