Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis
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Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The gene products hamartin and tuberin form the TSC complex that acts as GTPase-activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). Tuberin contains a RapGAP homology domain responsible for inactivation of Rheb, but functions of other protein domains remain elusive. Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation. The structure of the TSC2 N-terminal domain from Chaetomium thermophilum and a homology model of the human tuberin N terminus are presented. We characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mutations in tuberin. Many mutations are structural and produce improperly folded protein, explaining their effect in pathology, but we identify one point mutant that abrogates complex formation without affecting protein structure. We provide the first structural information on TSC2/tuberin with novel insight into the molecular function.
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The N-terminal TSC2 fragment is sufficient to pull down the full-length and C-terminal half of TSC1, and these interacting regions are conserved in the human proteins.
“This fragment of TSC2 was also shown to be sufficient to pull down the full-length, and C-terminal half of, TSC1, and these interacting regions are conserved in the human proteins (Zech et al., 2016).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Zech et al., 2016
A crystal structure of a stable N-terminal TSC2 fragment from C. thermophilum forms an α-solenoid constituting nine HEAT repeats.
“This TSC2 N-terminal fragment, like the S. pombe TSC1 core domain, forms an α-solenoid constituting nine HEAT repeats.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Zech et al., 2016
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Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12 · see citing works
- Authors
- Zech, R., Kiontke, S., Mueller, U., Oeckinghaus, A., & Kümmel, D.
- Affiliations
- Osnabrück University (DE)
- University of Münster (DE)
- Corresponding author
- Kümmel, Daniel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 291
- Issue
- 38
- Pages
- 20008-20020
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5025687
- OpenAlex
- W2490098155
- Cited by
- 29
- References
- 62
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 1 · 2018: 5 · 2017: 2
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HZB Repository (Helmholtz-Zentrum Berlin für Materialien und Energie GmbH (HZB)) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KU 2531/2-1, SFB 944-P17, OE 531/2-1)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- tuberous sclerosis complex, TSC2, tuberin, TSC1, hamartin, protein complex formation, Chaetomium thermophilum, homology modeling, point mutations, protein misfolding, mTORC1, tumor suppressor, protein-protein interaction
- MeSH terms
- Protein Domains, Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Chaetomium, Fungal Proteins, Humans, Neuropeptides, Tuberous Sclerosis, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Structural Homology, Protein, Multiprotein Complexes, HEK293 Cells, TOR Serine-Threonine Kinases
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