Novel modes of heterotrimeric G protein regulation

细胞通过感受器相互沟通并识别环境的变化，感受器可以探测到特定的化学或物理信号。大多数受体通过激活细胞内的第二种蛋白质来产生作用，这种蛋白质被称为G蛋白。然后，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的外部信号作出反应。此外，细胞内还有辅助蛋白调节受体触发的G蛋白效应。例如，为了对抗受体的激活作用，有一些蛋白质的作用是关闭G蛋白（RGS蛋白）或阻止G蛋白（golocoprotein）的开启。有趣的是，已经发现了几种调节蛋白，它们包含以不同方式作用于G蛋白的多个结构域。在某些情况下，这些功能看起来要么是多余的，要么是相互矛盾的，至少根据我们对它们的生物化学的了解是这样的。例如，蛋白质rgs14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。还有另一种基于goloco的蛋白质，称为G18，已知可以阻止G蛋白的激活，但我们的实验室发现，这种蛋白质分子中以前未被表征的部分可以起到相反的作用，即促进G蛋白的激活。这些复杂蛋白质的存在强烈地表明，细胞处理受体信号的方式尚未被发现。这些拟进行的研究将探讨RGS14和G18的多个G蛋白相互作用结构域如何协同工作以控制受体信号。这将增加我们对细胞如何相互沟通以及如何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.