InterPro domain: IPR009076

The macrolide antibiotic rapamycin and the cytosol protein FKBP12 can form a complex which specifically inhibits the TORC1 complex, leading to growth arrest. The FKBP12-rapamycin complex interferes with TORC1 function by binding to the FKBP12-rapamycin binding domain (FRB) of the Tor proteins.

This entry represents the FRB domain [ 1 , 2 ]. Proteins containing this domain include Tor proteins which are serine/threonine kinases conserved from fungi to humans. While higher eukaryotes such as humans possess a single Tor protein, yeasts contain two (Tor1 and Tor2) [ 3 ].

In budding yeast, the Tor2 protein exists in two distinct multi-component complexes, TORC1 and TORC2. TORC1 regulates cell growth by regulating many growth-related processes and is rapamycin sensitive, while TROC2 regulates the cell cytoskeleton and is rapamycin insensitive. Budding yeast TORC1 consists of either Tor1 or Tor2 in complex with Kog1, Lst8 and Tco89, while TORC2 is composed of Avo1, Avo2, Tsc11, Lst8, Bit61, Slm, Slm2 and Tor2 [ 4 , 4 ]. In both yeast and mammals, FKBP12-rapamycin binds to Tor (Tor1, Tor2, or mTOR) in TORC1, but not to Tor (Tor2 or mTOR) in TORC2. It has been suggested that the architecture of TORC2 or its unique composition might be responsible for the observed rapamycin resistance [ 5 ].

1. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239-42
2. Ubiquitin regulates TORC1 in yeast Saccharomyces cerevisiae. Mol. Microbiol. 58, 977-88
3. Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. Mol. Cell
4. The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2. Mol. Biol. Cell 16, 1883-900