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

被引：35

作者：

Fitzian, Katharina ^{[1
]}

Bruckner, Anne ^{[1
,2
,13
]}

Brohee, Laura ^{[3
]}

Zech, Reinhard ^{[4
,13
]}

Antoni, Claudia ^{[5
]}

Kiontke, Stephan ^{[4
,6
]}

Gasper, Raphael ^{[7
]}

Matos, Anna Livia Linard ^{[8
]}

Beel, Stephanie ^{[2
]}

Wilhelm, Sabine ^{[3
]}

Gerke, Volker ^{[2
]}

Ungermann, Christian ^{[9
,10
]}

Nellist, Mark ^{[11
]}

Raunser, Stefan ^{[5
]}

Demetriades, Constantinos ^{[3
,12
]}

Oeckinghaus, Andrea ^{[2
]}

Kummel, Daniel ^{[1
,4
]}

机构：

[1] Univ Munster, Inst Biochem, D-48149 Munster, Germany

[2] Univ Munster, Inst Mol Tumor Biol, D-48149 Munster, Germany

[3] Max Planck Inst Biol Ageing MPI AGE, D-50931 Cologne, Germany

[4] Univ Osnabruck, Dept Biol Chem, Struct Biol Sect, D-49076 Osnabruck, Germany

[5] Max Planck Inst Mol Physiol, Dept Struct Biochem, D-44227 Dortmund, Germany

[6] Philipps Univ Marburg, Fac Biol, Dept Plant Physiol & Photobiol, D-35032 Marburg, Germany

[7] Max Planck Inst Mol Physiol, Crystallog & Biophys Unit, D-44227 Dortmund, Germany

[8] Univ Osnabr, Inst Med Biochem, ZMBE, D-48149 Munster, Germany

[9] Univ Osnabrusk, Dept Biol Chem, Biochem Sect, D-49076 Osnabruck, Germany

[10] Univ Osnabrusk, Ctr Cellular Nanoanalyt CellNanOs, D-49076 Osnabruck, Germany

[11] Erasmus MC, Dept Clin Genet, NL-3015 CN Rotterdam, Netherlands

[12] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[13] Sanofi Aventis Deutschland GmbH, Ind Affairs, Diabet & Biosynth Operat, D-65926 Frankfurt, Germany

来源：

MOLECULAR CELL | 2021年 / 81卷 / 13期

基金：

欧洲研究理事会;

关键词：

TUBEROUS SCLEROSIS GENE; SMALL-ANGLE SCATTERING; FUNCTIONAL ASSESSMENT; STRUCTURAL BASIS; COLOCALIZATION; VARIANTS; GTPASE; KINASE; SUITE; IDENTIFICATION;

D O I：

10.1016/j.molcel.2021.04.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 PI3,5P(2), 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.

引用

页码：2705 / +

页数：26

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