Within every cell exists a network of proteins that directs life’s most fundamental processes. A protein in this network is the mechanistic target of rapamycin, or mTOR. It functions as a regulator, interpreting a wide array of signals from both inside and outside the cell to make decisions about growth, metabolism, and survival. mTOR acts as a command center that receives updates on the availability of resources like nutrients and energy. Based on this information, it orchestrates cellular responses, ensuring the cell behaves appropriately for its current conditions.
The Core mTOR Protein Blueprint
The mTOR protein is a large molecule, a type of enzyme known as a serine/threonine kinase. Its substantial size, consisting of 2,549 amino acids, is necessary to accommodate several distinct functional regions, or domains, each with a specific job. These domains are arranged in a precise sequence that dictates how the protein will fold and function. Four of these domains are particularly important to the protein’s overall structure and activity.
At one end of the protein lies the FAT domain, a large region that helps establish the overall shape and architecture of the mTOR molecule. Following this is the FRB domain, a small but notable section that serves as the specific binding site for the drug rapamycin when it is complexed with another protein called FKBP12. The heart of the protein is the kinase domain; this is the active part of mTOR that performs chemical reactions by attaching phosphate groups to other proteins to alter their function. At the very end of the protein chain is the FATC domain, which is needed for the stability and catalytic activity of the kinase domain.
These domains do not function in isolation but are intricately linked. The FAT domain wraps around the kinase domain, creating a scaffold that correctly positions it. The FRB domain is nestled within the kinase domain, positioning it to influence which proteins can access the active site. This integrated design allows the single mTOR protein to act as a highly regulated signaling molecule, ready to be incorporated into larger functional units.
Formation of the mTORC1 Complex
The core mTOR protein rarely acts alone. To carry out its diverse functions, it assembles with other specific proteins to form larger, more specialized machinery. The first of these major assemblies is known as mTOR Complex 1, or mTORC1. This complex consists of the mTOR protein, a large scaffolding protein called Raptor, and a stabilizing protein known as mLST8.
Each component of the mTORC1 structure has a defined purpose. The mTOR protein provides the central kinase activity, the engine that drives the complex’s function. The mLST8 protein binds to the kinase domain of mTOR, helping to stabilize it and maintain its active structure. The defining component is Raptor, which acts as a molecular scaffold and plays a primary role in recruiting the specific target proteins that mTORC1 will act upon.
The presence of Raptor makes mTORC1 a primary sensor of nutrient availability. When amino acids are abundant, mTORC1 is recruited to cellular organelles called lysosomes, allowing Raptor to capture target proteins like S6K1 and 4E-BP1, which regulate protein synthesis. The open accessibility of the FRB domain in this conformation allows the rapamycin-FKBP12 complex to bind, preventing Raptor from presenting substrates to the mTOR kinase and halting growth-promoting activities.
Assembly of the mTORC2 Complex
The core mTOR protein can also participate in a second, structurally and functionally distinct assembly called mTORC2. This complex shares the mTOR and mLST8 proteins with mTORC1, but its identity is defined by a different set of unique components that replace Raptor. The defining protein of this complex is Rictor, which serves a role analogous to Raptor but directs the complex toward different tasks.
The mTORC2 assembly consists of mTOR, mLST8, Rictor, and another protein called mSIN1. In this configuration, Rictor is the main scaffolding protein, making multiple contacts with the mTOR protein. The mSIN1 protein is also integral to the complex’s integrity, linking Rictor to mLST8 and stabilizing the overall structure.
The presence of Rictor and mSIN1 physically shields the FRB domain on the mTOR protein, making mTORC2 insensitive to rapamycin. This structure enables mTORC2 to respond to extracellular growth factors and phosphorylate a different set of targets, including the kinase Akt. Akt is a promoter of cell survival and helps organize the cell’s internal scaffolding, known as the cytoskeleton. This explains why acute rapamycin treatment does not affect mTORC2’s functions.
Connecting Structure to Cellular Regulation
The distinct architectures of mTORC1 and mTORC2 directly translate into their specialized roles in governing cellular life. The structure of each complex dictates which signals it can receive and which downstream processes it can control. This division of labor allows the cell to respond with precision to a wide variety of conditions, using the same core kinase in two different contexts.