CAREER: Evolution of Signaling Mechanisms in Membrane Receptors

许多生物医学过程和目标涉及膜蛋白（MP），其构成典型基因组中约25%的基因。由于MP部分可通过细胞外进入，因此它们形成了一组重要的蛋白质，用于潜在的生物工程应用。推进这些应用所需的MP的折叠和功能的基本理解是一个挑战，多年来一直落后于可溶性蛋白质。智力优势：PI提出，微生物感觉视紫红质已经进化成真核视紫红质，通过逐渐取代螺旋-螺旋接触的重要性与长距离接触形成折叠受体，以实现单一受体内的信号传导能力。本研究的目的是验证这一假说。PI提出，螺旋区和环区的氨基酸之间的三级接触发生在螺旋形成之前的非常早期阶段，可能发生在它们的结合过程中。两阶段假说是基于细菌视紫红质的实验研究。更广泛的影响。推进对膜受体信号机制的理解可能会提供新的方法来设计它们的功能。这对于潜在的应用非常重要，例如：-纳米生物技术，生物工程或医疗干预。有用的框架，以整合基本过程折叠和信号转导的研究-支持教育和研究人员和学生之间的合作与不同的背景， 现有的课程在爱丁堡大学本科生和（3）与高中学生夏令营在PI实验室-创建一个模块SAMS（夏季学院少数民族学生）在卡内基梅隆大学， 我有一个次要的任命。作为蛋白质学会青年蛋白质科学家委员会的主席，我将能够鼓励 在美国和欧洲的大学未来的学生分会从事类似的 外联活动。

Many biomedical processes and targets involve membrane proteins (MPs) which constitute approximately 25% of the genes in typical genomes. Since MPs are in part accessible through the outside of cells, they form an important group of proteins for potential bioengineering applications. Advancing the fundamental understanding of folding and function of MPs required for such applications is a challenge that has lagged behind that of soluble proteins for many years. Intellectual Merit.The PI proposes that microbial sensory rhodopsin has evolved into eukaryotic rhodopsin through gradual replacement of the importance of helix-helix contacts with long-range contacts to form the folded receptor in order to achieve signaling capabilities within a single receptor. It is the goal of this proposal to test this hypothesis.The PI proposes that tertiary contacts between amino acids from both helical and loop regions take place during the very early stages before the helices have formed and possibly during their association. The two-stage hypothesis was based on experimental studies of bacteriorhodopsin. Broader Impact. Advancing the understanding of signaling mechanisms in membrane receptors may provide novel ways to engineer their function.This would be important for potential uses such as:-nanobiotechnology,bioengineering or medical intervention.-useful framework to integrate study of the fundamental processes folding and signal transduction -support education of and collaboration between researchers and students with disparate backgrounds in existing courses at the University of Pittsburgh-undergraduate student and (3) with high-school students summer camp in the PIs laboratory -Create a module for SAMS (Summer Academy for Minority Students) at Carnegie Mellon University where I hold a secondary appointment. -As the Chair of the Young Protein Scientists Committee of the Protein Society, I will be able to encourage future student chapters at Universities throughout the United States and Europe to engage in similar outreach activities.