Control of Protein Dimerization through Light-Regulated Rapamycin

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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.