Recent progress in the study of the Rheb family GTPases

Abstract

In this review we highlight recent progress in the study of Rheb family GTPases. Structural studies using X-ray crystallography and NMR have given us insight into unique features of this GTPase. Combined with mutagenesis studies, these works have expanded our understanding of residues that affect Rheb GTP/GDP bound ratios, effector protein interactions, and stimulation of mTORC1 signaling. Analysis of cancer genome databases has revealed that several human carcinomas contain activating mutations of the protein. Rheb's role in activating mTORC1 signaling at the lysosome in response to stimuli has been further elucidated. Rheb has also been suggested to play roles in other cellular pathways including mitophagy and peroxisomal ROS response. A number of studies in mice have demonstrated the importance of Rheb in development, as well as in a variety of functions including cardiac protection and myelination. We conclude with a discussion of future prospects in the study of Rheb family GTPases.

Keywords: Lysosome; Mouse study; Mutants; Rheb GTPase; Structure; mTORC1.

Fig 1. Crystal Structure of Rheb1

A) The crystal structures of Rheb1 bound with GTP (blue) and Rheb1 bound with GDP (grey) were aligned. Only GTP, and not GDP, is shown colored in red. The structures are displayed as rotated 180° around the y-axis. B) Rheb protein, with a length of 184 amino acids, is represented with the approximate locations of the G-boxes 1–5 and CAAX motif. Crystal structures are from the Protein Data Bank (PDB ID: 1XTQ, 1XTS), reference [6].

Fig. 2. Rheb stimulates mTORC1 activity on the lysosomal membrane

A schematic representation of Rheb involvement in activation of mTORC1 on the lysosome (protein complexes are not to scale). Rheb localizes to the lysosomal membrane by its farnesylated C-terminal tail. Rheb bound GTP has been shown to stimulate mTORC1 activation at the lysosomal surface, and Rheb bound GDP does not. The TSC Complex, composed of TSC1, TSC2, and TBC1D7, stimulates Rheb GTPase activity and thus inhibits Rheb mediated mTORC1 stimulation.