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限制的细胞器，主要负责为活跃呼吸细胞的能量需求提供服务。围绕每个线粒体的外膜或包膜通过膜间空间与第二（或内）膜分离。线粒体外膜（TOM）的移位酶与线粒体内膜（TIM）的移位酶协作以介导未折叠的前蛋白进入线粒体。蛋白质在其活性折叠状态下通常体积庞大，因此前蛋白作为延伸的多肽链通过膜，因为它们通过的通道相对较窄。辅助前蛋白有助于前蛋白的识别和靶向，并有助于在它们通过孔移位之前将它们保持在未折叠状态，并随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机制的选定成分的三维原子级结构，使我们能够可视化分子细节中蛋白质易位某些方面的定格快照。结合最近的生物化学数据，这些信息将提供一个架构框架，我们可以使用它来帮助我们解释复杂的结构-功能之间的关系组件的TOM和其他蛋白质，他们整合他们的活动在易位事件。最终，这种基础研究将导致开发用于处理与人类线粒体缺陷相关的疾病的策略，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.