TI - Rheb binds and regulates the mTOR kinase . AB - BACKGROUND : The target of rapamycin ( TOR ) , in complex with the proteins raptor and LST8 (TOR complex 1) , phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation . Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb , and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal . The Tuberous Sclerosis heterodimer ( TSC1/TSC2 ) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo . RESULTS : Here , we show that Rheb binds to the TOR complex specifically , independently of its ability to bind TSC2 , through separate interactions with the mTOR catalytic domain and with LST8 . Rheb binding to the TOR complex in vivo and in vitro does not require Rheb guanyl nucleotide charging but is modulated by GTP and impaired by certain mutations ( Ile39Lys ) in the switch 1 loop . Nucleotide -deficient Rheb mutants , although capable of binding mTOR in vivo and in vitro , are inhibitory in vivo , and the mTOR polypeptides that associate with nucleotide -deficient Rheb in vivo lack kinase activity in vitro . Reciprocally , mTOR polypeptides bound to Rheb (Gln64Leu) , a mutant that is nearly 90% GTP charged , exhibit substantially higher protein kinase specific activity than mTOR bound to wild-type Rheb . CONCLUSIONS : The TOR complex 1 is a direct target of Rheb-GTP , whose binding enables activation of the TOR kinase .