This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cell growth is a fundamental biological process that determines the sizes of cells, organs, and organisms, and is often perturbed in human cancers. By integrating signals derived from nutrients, energy status, and growth factors, the mammalian target of rapamycin (mTOR) signaling network regulates the growth mechanisms. To this end, the long-term goal of our research is to determine the structures of several components within the mTOR pathway and to understand the basis for protein-protein interactions and their implications on the function of this growth regulation. To accomplish our goals, we plan to design and apply multidisciplinary experimental approaches, combining tools of structural biology, cell biology, and biochemistry.
We aim to understand in molecular detail how mTOR complexes propagate signals and then adapt to inputs from nutrients and growth factors. Therefore, in addition to determining the structures of the individual proteins and their functional domains with high-resolution x-ray diffraction, we will use SAXS to construct intermediate-resolution envelopes of high molecular weight complexes, as well as to track associations and domain motions in solution. We underscore the importance of synchrotron radiation to our structural studies of the mTOR pathway. With the results obtained through successful SAXS experiments, we will create an adequate framework in which the high-resolution models that are generated by protein crystallography can be meaningfully fitted. Moreover, this study will provide new insights into understanding the protein-protein interactions, docking geometries, and stoichiometry of binding within the mTOR signaling pathway.
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