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Published on: January 7, 2019

Structural analysis and functional implications of the negative mTORC1 regulator REDD1

Silvia Vega-Rubin-de-Celis1, Zeina Abdallah, Lisa Kinch

  • 1Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Biochemistry
|February 20, 2010
PubMed

Insights

The stress-response protein REDD1 inhibits mTORC1, a key regulator of cell growth implicated in cancer. Structural and functional studies reveal a novel REDD1 domain essential for this inhibition, clarifying its mechanism.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Structural Biology

Background:

  • The stress-response protein REDD1 regulates mTORC1, a critical pathway for cell growth and proliferation implicated in cancer.
  • REDD1 is induced by hypoxia and inhibits mTORC1, a process dependent on the TSC1/TSC2 complex.
  • Previous models proposed REDD1 inhibits mTORC1 by sequestering 14-3-3 proteins away from TSC2.

Purpose of the Study:

  • To elucidate the structural basis of REDD1 function and its mechanism of mTORC1 inhibition.
  • To identify essential functional segments within REDD1 through structure/function analyses.
  • To investigate the interaction of REDD1 with regulatory proteins like 14-3-3 and TSC2.

Main Methods:

  • X-ray crystallography to determine the 3D structure of REDD1 at 2.0 A resolution.
  • Structure-based docking and functional assays to analyze protein interactions.
  • Mutagenesis studies and sequence conservation mapping to identify critical functional regions.

Main Results:

  • A novel domain in REDD1, formed by two interdependent segments, was identified with a unique alpha/beta sandwich fold.
  • Structure-based analyses suggest REDD1 does not directly bind to 14-3-3 proteins.
  • A critical interaction hotspot on the REDD1 surface was mapped, essential for mTORC1 inhibition.

Conclusions:

  • REDD1 possesses a novel structural domain crucial for its function in inhibiting mTORC1.
  • The mechanism of REDD1-mediated mTORC1 inhibition does not involve direct binding to 14-3-3 proteins.
  • Identification of a key interaction site provides a target for understanding REDD1's role in cancer and stress response.

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