NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38.

Ras homolog enriched in brain (Rheb) is a small GTPase that regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and, thereby, cell growth and metabolism. Here we show that cycling between the inactive GDP-and the active GTP-bound state modulates the backbone dynamics of a C-terminal truncated form, RhebDCT, which is suggested to influence its interactions. We further investigated the interactions between RhebDCT and the proposed Rheb-binding domain of the regulatory protein FKBP38. The observed weak interactions with the GTP-analogue(GppNHp-) but not the GDP-bound state, appear to accelerate the GDP to GTP exchange, but only very weakly compared to a genuine GEF. Thus, FKBP38 is most likely not a GEF but a Rheb effector that may function in membrane targeting of Rheb.