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Architecture of the Tuberous Sclerosis Protein Complex

Kailash Ramlaul, Wencheng Fu, Hua Li, Natàlia de Martin Garrido, Lin He, Wei Cui, Christopher H S Aylett, View ORCID ProfileGeng Wu
doi: https://doi.org/10.1101/2020.09.29.319707
Kailash Ramlaul
1Section for Structural Biology, Department of Medicine, Imperial College London, Exhibition Road, London, SW7 2BB, United Kingdom
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Wencheng Fu
2State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, The Joint International Research Laboratory of Metabolic & Developmental Sciences MOE, Shanghai Jiao Tong University, Shanghai, China
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Hua Li
2State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, The Joint International Research Laboratory of Metabolic & Developmental Sciences MOE, Shanghai Jiao Tong University, Shanghai, China
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Natàlia de Martin Garrido
1Section for Structural Biology, Department of Medicine, Imperial College London, Exhibition Road, London, SW7 2BB, United Kingdom
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Lin He
3Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
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Wei Cui
4Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, United Kingdom
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Christopher H S Aylett
1Section for Structural Biology, Department of Medicine, Imperial College London, Exhibition Road, London, SW7 2BB, United Kingdom
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  • For correspondence: c.aylett@imperial.ac.uk geng.wu@sjtu.edu.cn
Geng Wu
2State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, The Joint International Research Laboratory of Metabolic & Developmental Sciences MOE, Shanghai Jiao Tong University, Shanghai, China
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  • ORCID record for Geng Wu
  • For correspondence: c.aylett@imperial.ac.uk geng.wu@sjtu.edu.cn
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Abstract

The Tuberous Sclerosis Complex (TSC) protein complex (TSCC), comprising of three subunits TSC1, TSC2, and TBC1D7, is widely recognised as a key integration hub for cell growth and intracellular stress signals upstream of the mammalian target of rapamycin complex 1 (mTORC1). The TSCC negatively regulates mTORC1 by acting as a GTPase-activating protein (GAP) towards the small GTPase Rheb. Both human TSC1 and TSC2 are important tumor suppressors, and their mutations underlie the tuberous sclerosis disease.

We used single-particle cryo-EM to reveal the organisation and architecture of the complete human TSCC. We show that TSCC forms an elongated scorpion-like structure, consisting of a “body” in the middle, and a “pincer” and a “tail” at each side. The “body” is composed of a flexible TSC2 HEAT repeat dimer, along the inner surface of which runs the TSC1 coiled-coil backbone, breaking the symmetry of the dimer. Each end of the body is structurally distinct, representing the N- and C-termini of TSC1; a “pincer” is formed by the highly flexible N-terminal TSC1 core domains and a barbed “tail” makes up the TSC1 coiled-coil-TBC1D7 junction. The TSC2 GAP domain is found abutting the centre of the body on each side of the dimerisation interface, poised to bind a pair of Rheb molecules at a similar separation to the pair in activated mTORC1.

Our architectural dissection reveals the mode of association and topology of the complex, casts light on the recruitment of Rheb to the TSCC, and also hints at functional higher order oligomerisation, which has previously been predicted to be important for Rheb-signalling suppression.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 01, 2020.
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Architecture of the Tuberous Sclerosis Protein Complex
Kailash Ramlaul, Wencheng Fu, Hua Li, Natàlia de Martin Garrido, Lin He, Wei Cui, Christopher H S Aylett, Geng Wu
bioRxiv 2020.09.29.319707; doi: https://doi.org/10.1101/2020.09.29.319707
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Architecture of the Tuberous Sclerosis Protein Complex
Kailash Ramlaul, Wencheng Fu, Hua Li, Natàlia de Martin Garrido, Lin He, Wei Cui, Christopher H S Aylett, Geng Wu
bioRxiv 2020.09.29.319707; doi: https://doi.org/10.1101/2020.09.29.319707

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