Control of Protein Dimerization through Light-Regulated Rapamycin

通过这个奖项，化学系的生命过程化学项目资助匹兹堡大学的Alexander Deiters开发一种新型的分子“胶”，可以用来将两个蛋白质分子结合在一起，从而控制各种生物功能。在这个研究项目中开发的新型“胶”类似于一种自然产生的物质雷帕霉素，它被广泛用于结合成对的蛋白质。这种新物质与雷帕霉素不同，因为它有一个光敏开关。这一开关允许研究人员随意开启和关闭蛋白质结合过程，从而产生了一种强大的新工具。这项研究正在开辟各种各样可能的新应用，这可能会对许多生物和医学研究领域产生广泛影响。研究人员正在进一步扩大他们工作的影响，与一家儿童博物馆合作，开发演示和展览，为幼儿及其父母带来基本的生物事件，特别是那些涉及紫外线与组织相互作用的事件。在这个项目中，研究人员正在开发光响应型雷帕霉素类似物，用于光学控制蛋白质二聚和其他细胞过程。雷帕霉素是一种常用的生物分子工具，已被用来控制广泛的生理过程。其调控的细胞功能广泛，包括转录、信号转导、蛋白质定位、酶激活、蛋白质剪接、蛋白质分泌和蛋白质翻译后修饰等。雷帕霉素通过招募FKBP和FRB形成稳定的三元复合体，作为蛋白质二聚的小分子诱导剂发挥作用。通过设计和合成雷帕霉素的光敏类似物，正在开发一种通用且普遍适用的光调节方法，适用于许多生物应用。光代表了一种创新的外部控制元素，因为a)它与绝大多数细胞过程是正交的，b)它是微创的，c)它可以以非常高的空间和时间分辨率进行控制。光激活的雷帕霉素类似物与融合在FKBP和FRB上的不同蛋白质相结合，将能够对广泛的细胞过程进行光学调节，包括蛋白质功能、蛋白质定位和蛋白质结合。研究目标的完成将导致1)开发用于多波长激活多个细胞过程的正交笼式雷帕霉素-FKBP对，以及2)通过光可切换基序修饰的雷帕霉素类似物实现生物过程的可逆光开关。拟议研究的预期结果是对各种细胞过程的时空控制的统一方法。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Alexander Deiters of the University of Pittsburgh to develop a new type of molecular "glue" that can be used to bind together two molecules of protein and, thus, control a variety of biological functions. The new type of "glue" being developed in this research project is similar to a naturally occurring substance known as rapamycin that has been extensively used to bind pairs of proteins. The new substance differs from rapamycin since it has a light-sensitive switch. This switch allows the investigators to turn on and off the protein-binding process at will, producing a powerful new tool. This research is opening up a wide variety of possible new applications that would potentially have a broad impact on a number of biological and medical fields of study. The investigators are further broadening the impact of their work by partnering with a children's museum to develop demonstrations and exhibits that bring basic biological events, especially those involving the interaction of ultraviolet light with tissues, to life for young children and their parents.In this project, the investigators are developing light-responsive rapamycin analogs for the optical control of protein dimerization and other cellular processes. Rapamycin is a commonly applied biomolecular tool that has been used to control a wide range of physiological processes. An extensive number of cellular functions have been brought under its control, including transcription, signal transduction, protein localization, enzyme activation, protein splicing, protein secretion, and protein post-translational modification in cells. Rapamycin functions as a small molecule inducer of protein dimerization by recruiting FKBP and FRB to form a stable ternary complex. A versatile and generally applicable light-regulation methodology that is adaptable to numerous biological applications is being developed by designing and synthesizing light-sensitive analogs of rapamycin. Light represents an innovative external control element, since a) it is orthogonal to the vast majority of cellular processes, b) it is minimally invasive, and c) it can be controlled with very high spatial and temporal resolution. Light-activated analogs of rapamycin, in conjunction with different proteins fused to FKBP and FRB, will enable the optical regulation of a wide range of cellular processes, including protein function, protein localization, and protein association. Completion of the research objectives will lead to 1) the development of orthogonal caged rapamycin-FKBP pairs for the multi-wavelength activation of multiple cellular processes, and 2) the reversible light-switching of biological processes through rapamycin analogs modified with photo-switchable motifs. Expected outcomes of the proposed research are a unifying approach for the spatio-temporal control of various cellular processes.