Reversible modification of methionine as a mechanism to regualte protein function in the mitochondrion and secretory pathway

细胞和组织的功能通常由蛋白质调节，这些蛋白质可以通过可逆的修饰来开启或关闭。这些细胞功能包括细胞分裂、新陈代谢和死亡等关键过程，因此我们了解这些可逆修饰是如何发生的是很重要的。该项目旨在研究一种特征不佳的修饰，称为蛋氨酸氧化，它可以在细胞应激条件下发生。具体地说，我们将获得关于特定酶催化蛋白质氧化和还原的能力的详细信息--本质上能够开启和关闭蛋白质功能。因此，这项研究有可能揭开在正常生理和应激状态下调节细胞功能的关键机制。为了更全面地了解这种酶，我们将确定其在催化循环中的三维结构，从而对其工作原理有一个详细的了解。我们还将开发新的化学探针，使我们能够在活细胞内跟踪其酶活性，提供其在正常和应激条件下的位置和活性的前所未有的详细信息。最后，我们将使用我们对酶机制的知识来确定酶的底物，换句话说，它能够打开和关闭的蛋白质。利用这些信息，我们将了解酶的工作方式、地点和时间，并解开由其活性控制的细胞功能。

The function of cells and tissues is often regulated by proteins that can be switched on or off by their reversible modification. These cellular function include critical processes such as cell-division, metabolism and death so it is important that we understand how these reversible modifications occur. This project aims to study one type of poorly characterised modification, called methionine oxidation, which can occur during conditions of cell stress. Specifically we will gain detailed information on the ability of a specific enzyme to catalyse both the oxidation and reduction of proteins - essentially being able to switch on and off protein function. Hence, the research has the potential to unravel a key mechanism for regulating cellular function during normal physiology and during stress.To understand this enzyme more fully, we will determine its 3-dimensional structure during its catalytic cycle and in that way obtain a detailed understanding of how it works. We will also develop new chemical probes which will enable us to follow its enzymatic activity within live cells providing unprecedented detail on its location and activity under normal and stress conditions. Finally, we will use our knowledge of the enzyme's mechanism to identify the substrates of the enzyme, in other words, the proteins it is able to turn on and off. Using this information we will understand how, where and when the enzyme works and unravel the cellular functions that are controlled by its activity.