Molecular basis of the acceleration of the GDP-GTP exchange of human ras homolog enriched in brain by human translationally controlled tumor protein.

ABSTRACT: Ras homolog enriched in brain (Rheb), a small GTPase, positively regulates the mTORC1 pathway. The GDP-GTP exchange of Rheb has been suggested to be facilitated by translationally controlled tumor protein (TCTP). Here we demonstrate that human TCTP (hTCTP) interacts with human Rheb (hRheb) and accelerates its GDP release in vitro and that hTCTP activates the mTORC1 pathway in vivo. To investigate the underlying mechanism, we built structure models of GDP- and GTP-bound hRheb in complexes with hTCTP and performed molecular dynamics simulations of the models, which predict key residues involved in the interactions and region of hRheb undergoing conformational change during the GDP-GTP exchange. These results are verified with site-directed mutagenesis and in vitro biochemical and in vivo cel

SUBMITTER: Dong X 

PROVIDER: S-EPMC2749149 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature