Novel modes of heterotrimeric G protein regulation

细胞之间相互通信，通过使用感受器来识别环境的变化，这些感受器可以检测特定的化学或物理信号。大多数受体通过激活细胞内另一种称为G蛋白的蛋白质来发挥作用。然后，被激活的G蛋白能够对其他细胞过程产生影响，从而允许细胞以适当的方式对原始外部信号做出反应。此外，细胞内还有辅助蛋白质，调节由受体激活的G蛋白效应。例如，为了对抗受体的激活效应，有一些蛋白质的作用要么是关闭G蛋白(RGS蛋白)，要么是阻止G蛋白被打开(GoLocoProteins)。有趣的是，已经发现了几种包含多个结构域的调控蛋白，这些结构域可以以不同的方式作用于G蛋白。在某些情况下，这些功能似乎要么是多余的，要么是彼此不一致的，至少根据我们对它们生物化学的了解是这样的。例如，RGS14蛋白同时具有阻止G蛋白激活(通过其GoLoco基序)和关闭激活的G蛋白(通过其RGS结构域)的潜力。还有另一种已知的基于GoLoco的蛋白质G18可以防止G蛋白激活，但我们的实验室发现，该蛋白质分子中以前未描述的部分可以起相反的作用，即它促进G蛋白激活。这些复合体蛋白的存在强烈表明，细胞处理受体信号的方式尚未被发现。拟议的研究将探讨RGS14和G18的多个G蛋白相互作用结构域的组合功能如何共同控制受体信号。这将增加我们对细胞如何相互交流和对环境变化做出反应的理解。

Cells communicate with one another and recognize changes in their environment through the use of receptorswhich detect specific chemical or physical signals. The majority of receptors produce their effects byactivating a second protein inside the cell known as a G protein. The activated G protein then is able to produceeffects on other cellular processes, thus allowing the cell to respond in an appropriate way to the originalexternal signal. In addition, there are auxiliary proteins inside the cell that regulate the G protein effectstriggered by the receptors. For example, to counter the activating effects of receptors there are proteins whosejob it is to either turn G proteins off (RGS proteins) or prevent G proteins from being turned on (GoLocoproteins). Intriguingly, several regulatory proteins have been discovered that contain multiple domains that canact on G proteins in different ways. In some cases, these functions appear to be either redundant or at oddswith one another, at least based on what we know about their biochemistry. For example, the protein RGS14simultaneously has the potential to both prevent G protein activation (via its GoLoco motif) and turn offactivated G proteins (via its RGS domain). There is another GoLoco-based protein known as G18 that isknown to prevent G protein activation, but our laboratory has found that a previously uncharacterized part ofthis protein molecule can do the opposite, that is, it promotes G protein activation. The existence of thesecomplex proteins strongly suggests that there are undiscovered ways in which cells deal with receptor signals.The proposed studies will investigate how the combined functions of the multiple G protein-interactingdomains of RGS14 and G18 work together to control receptor signals. This will increase our understanding ofhow cells communicate with each other and respond to changes in their environment.