2. Academic Validation
  3. TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation

TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation

  • Mol Cell. 2021 Jul 1;81(13):2705-2721.e8. doi: 10.1016/j.molcel.2021.04.019.
Katharina Fitzian 1,  Anne Brückner 2,  Laura Brohée 3,  Reinhard Zech 4,  Claudia Antoni 5,  Stephan Kiontke 6,  Raphael Gasper 7,  Anna Livia Linard Matos 8,  Stephanie Beel 9,  Sabine Wilhelm 3,  Volker Gerke 8,  Christian Ungermann 10,  Mark Nellist 11,  Stefan Raunser 5,  Constantinos Demetriades 12,  Andrea Oeckinghaus 13,  Daniel Kümmel 14
Affiliations

Affiliations

  • 1 University of Münster, Institute of Biochemistry, 48149 Münster, Germany.
  • 2 University of Münster, Institute of Biochemistry, 48149 Münster, Germany; University of Münster, Institute of Molecular Tumor Biology, 48149 Münster, Germany.
  • 3 Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany.
  • 4 University of Osnabrück, Department of Biology/Chemistry, Structural Biology Section, 49076 Osnabrück, Germany.
  • 5 Max Planck Institute of Molecular Physiology, Department of Structural Biochemistry, 44227 Dortmund, Germany.
  • 6 University of Osnabrück, Department of Biology/Chemistry, Structural Biology Section, 49076 Osnabrück, Germany; Philipps-University Marburg, Faculty of Biology, Department of Plant Physiology and Photobiology, 35032 Marburg, Germany.
  • 7 Max Planck Institute of Molecular Physiology, Crystallography and Biophysics Unit, 44227 Dortmund, Germany.
  • 8 University of Münster, Institute of Medical Biochemistry, ZMBE, 48149 Münster, Germany.
  • 9 University of Münster, Institute of Molecular Tumor Biology, 48149 Münster, Germany.
  • 10 University of Osnabrück, Department of Biology/Chemistry, Biochemistry Section & Center of Cellular Nanoanalytics (CellNanOs), 49076 Osnabrück, Germany.
  • 11 Department of Clinical Genetics, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands.
  • 12 Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany; University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany. Electronic address: demetriades@age.mpg.de.
  • 13 University of Münster, Institute of Molecular Tumor Biology, 48149 Münster, Germany. Electronic address: oeckinga@ukmuenster.de.
  • 14 University of Münster, Institute of Biochemistry, 48149 Münster, Germany; University of Osnabrück, Department of Biology/Chemistry, Structural Biology Section, 49076 Osnabrück, Germany. Electronic address: daniel.kuemmel@wwu.de.
PMID: 33974911 DOI: 10.1016/j.molcel.2021.04.019
Abstract

The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P2, demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.

Keywords

TSC; X-ray crystallography; lysosomes; mTORC1; membrane binding; phosphatidylinositol phosphate.

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