Structural analysis and functional implications of the negative mTORC1 regulator REDD1

Silvia Vega-Rubin-de-Celis, Zeina Abdallah, Lisa Kinch, Nick V. Grishin, James Brugarolas, Xuewu Zhang

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

REDD1 is a conserved stress-response protein that regulates mTORCl, a critical regulator of cell growth and proliferation that is implicated in cancer. REDD1 is induced by hypoxia, and REDD1 overexpression is sufficient to inhibit mTORC1. mTORC1 is regulated by the small GTPase Rheb, which in turn is regulated by the GTPase-activating protein complex, TSC1/TSC2. REDD1 induced-mTORC1 inhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to TSC2-depedent inhibition of mTORC1. Structure/function analyses have led us to identify two segments in REDD1 that are essential for function, which act in an interdependent manner. We have determined a crystal structure of REDD1 at 2.0 Å resolution, which shows that these two segments fold together to form an intact domain with a novel fold. This domain is characterized by an α/β sandwich consisting of two antiparallel α-helices and a mixed. β-sheet encompassing an uncommon psi-loop motif. Structure-based docking and functional analyses suggest that REDD1 does not directly bind to 14-3-3 proteins. Sequence conservation mapping to the surface of the structure and mutagenesis studies demarcated a hotspot likely to interact with effector proteins that is essential for REDD1-mediated mTORC1 inhibition.

Original languageEnglish (US)
Pages (from-to)2491-2501
Number of pages11
JournalBiochemistry
Volume49
Issue number11
DOIs
StatePublished - Mar 23 2010

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Structural analysis
14-3-3 Proteins
GTPase-Activating Proteins
Mutagenesis
Monomeric GTP-Binding Proteins
Cell proliferation
Cell growth
Heat-Shock Proteins
Conservation
Proteins
Crystal structure
Cell Proliferation
mechanistic target of rapamycin complex 1
Growth
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

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Structural analysis and functional implications of the negative mTORC1 regulator REDD1. / Vega-Rubin-de-Celis, Silvia; Abdallah, Zeina; Kinch, Lisa; Grishin, Nick V.; Brugarolas, James; Zhang, Xuewu.

In: Biochemistry, Vol. 49, No. 11, 23.03.2010, p. 2491-2501.

Research output: Contribution to journalArticle

Vega-Rubin-de-Celis, Silvia ; Abdallah, Zeina ; Kinch, Lisa ; Grishin, Nick V. ; Brugarolas, James ; Zhang, Xuewu. / Structural analysis and functional implications of the negative mTORC1 regulator REDD1. In: Biochemistry. 2010 ; Vol. 49, No. 11. pp. 2491-2501.
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