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

Full 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 cell biological analyses. Furthermore, a crystal structure of the E12V mutant hTCTP, which lacks the guanine nucleotide exchange factor activity, shows that the deficiency appears to be caused by loss of a salt-bridging interaction with Lys-45 of hRheb. These data collectively provide insights into the molecular mechanisms of how hTCTP interacts with hRheb and activates the mTORC1 pathway.

Author information

Author/s: Dong, Xianchi (X); Yang, Bei (B); Li, Yingjie (Y); Zhong, Chen (C); Ding, Jianping (J);

Affiliation: State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2009-Aug; vol 284 (issue 35) : pp 23754-64

Dates: Created 2009/08/24; Completed 2009/10/19;

PMID: 19570981, status: MEDLINE (last retrieved date: 10/19/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Binding Sites
Cell Line
Guanosine Diphosphate - metabolism
Guanosine Triphosphate - metabolism
Humans
Molecular Conformation
Monomeric GTP-Binding Proteins - chemistry; genetics; metabolism

Monomeric GTP-Binding Proteins - chemistry; genetics; metabolism
Neuropeptides - chemistry; genetics; metabolism
Protein Binding
Protein Structure, Secondary
Signal Transduction
Transcription Factors - genetics; metabolism
Tumor Markers, Biological - chemistry; genetics; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Neuropeptides (0) ; RHEB protein, human (0) ; Transcription Factors (0) ; Tumor Markers, Biological (0) ; mTORC1 protein, human (0) ; translationally controlled tumor protein, p23 (0) ; Guanosine Diphosphate (146-91-8) ; Guanosine Triphosphate (86-01-1) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)

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