Abstract
The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.
Highlights
The Target of Rapamycin (TOR) (Target Of Rapamycin) genes were first identified in a screen of yeast mutants that were resistant to the macrolide rapamycin [1], a compound produced by the soil bacterium Streptomyces hygroscopicus collected by bioprospectors from Easter Island in the 1960s [2]
The encoded Tor protein was to become the founding member of the family of Phosphatidylinositol 3-kinase-related kinases (PIKKs) [3] – Ser/Thr-protein kinases with curious sequence similarity to phosphatidylinositol-3 kinases (PIKs)
In part due to improvements in cryo-electron microscopy, there has been an explosion of available structural information for both (m)TOR complexes, related PIKKs, and (m)TORC1 regulators which we review here (Tables 1 and 2)
Summary
The TOR (Target Of Rapamycin) genes were first identified in a screen of yeast mutants that were resistant to the macrolide rapamycin [1], a compound produced by the soil bacterium Streptomyces hygroscopicus collected by bioprospectors from Easter Island in the 1960s [2]. Structural studies have shown that PRAS40 can bind both to Raptor via its TOS motif and to the mTOR FRB domain via an amphipathic helix, similar to p70S6K (Figure 2C) [17]. This helix is connected by a disordered segment to a beta-strand that interacts with mLst and stabilizes the interaction. The structure of the mTORC1-Rheb complex shows that Rheb binds both the HEAT and FAT domains of mTOR on an interface opposite to the active site (Figure 3D) [17]. Some mutations have been shown to reduce binding to the negative
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