MTor Structure

A number laboratories identified mTOR (FRAP, RAFT1, SEP) around the same time (8,12-14). Cloning and sequence analysis revealed that mTOR was a 289-kDa serine threonine kinase with approx 44% homology to the yeast TORs. The homology in the C-terminus of mTOR with the catalytic kinase domain (CD) of the lipid kinase phospho-insitide-3 kinase (PI3K) led to its characterization as a phosphotidylinositol-3 kinase related protein kinase (PIKK) (15). Members of the PIKK family include TEL1, ATM, ATR, and TRRAP. There are a number of HEAT repeats (Huntington, EF3, A subunit of PP2A, TOR1) present in the amino terminus half of the protein that are thought to mediate protein-protein interactions (Fig. 1) (16). There is also a FAT (FRAP, ATM, TRRAP) and FATC domain that are thought to modulate kinase activity, possibly by interaction with each other (17). The FRB (FKBP12 rapamycin-binding domain) is required for binding of the rapamycin FKBP12 complex to mTOR (18,19). Point mutations within this domain generate rapamycin-resistant forms of mTOR (18). The RD (regulatory domain) region of mTOR contains sites that are phosphorylated in response to growth factors, although it is not clear exactly how this phosphorylation affects mTOR function (20-22).

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