Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)
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Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the occurrence of benign tumors in various vital organs and tissues. TSC1 and TSC2, the TSC1 and TSC2 gene products, form the TSC protein complex that senses specific cellular growth conditions to control mTORC1 signaling. TBC1D7 is the third subunit of the TSC complex, and helps to stabilize the TSC1-TSC2 complex through its direct interaction with TSC1. Homozygous inactivation of TBC1D7 causes intellectual disability and megaencephaly. Here we report the crystal structure of a TSC1-TBC1D7 complex and biochemical characterization of the TSC1-TBC1D7 interaction. TBC1D7 interacts with the C-terminal region of the predicted coiled-coil domain of TSC1. The TSC1-TBC1D7 interface is largely hydrophobic, involving the α4 helix of TBC1D7. Each TBC1D7 molecule interacts simultaneously with two parallel TSC1 helices from two TSC1 molecules, suggesting that TBC1D7 may stabilize the TSC complex by tethering the C-terminal ends of two TSC1 coiled-coils.
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As supported by analytical ultracentrifugation data from both studies, the exact stoichiometry of the TBC1D7-TSC1 coiled-coil interaction appears to be dependent on the ratio between the two molecules, and this may underlie physiologic activity of TBC1D7 in regulating TSCC oligomerisation.
“As supported by analytical ultracentrifugation data from both studies (Gai et al., 2016a; Qin et al., 2016), the exact stoichiometry of the TBC1D7-TSC1 coiled-coil interaction appears to be dependent on the ratio between the two molecules, and this may underlie physiologic activity of TBC1D7 in regulation TSCC oligomerisation.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Qin et al., 2016
Both TBC1D7-TSC1 crystal structures highlight a conserved interaction interface, with a long helix from TBC1D7 packing against the TSC1 coiled-coil to form a three-helix bundle.
“Both TBC1D7-TSC1 crystal structures highlight a conserved interaction interface, with a long helix from TBC1D7 packing against the TSC1 coiled-coil to form a three-helix bundle.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Qin et al., 2016
In the complex solved by Qin et al., two TBC1D7 and four TSC1 molecules per asymmetric unit, whereby each TBC1D7 complexed with two TSC1 molecules, forming a triple helical bundle; the last ~15 residues of each TSC1 molecule were not visible.
“In contrast, the complex solved by Qin et al. shows two TBC1D7 and four TSC1 molecules per asymmetric unit, whereby each TBC1D7 complexed with two TSC1 molecules, forming a triple helical bundle (Fig. 5F). In this structure, the last ~15 residues of each TSC1 molecule – which formed the kinked helix in the crystal structure by Gai et al. – were not visible.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Qin et al., 2016
In both TBC1D7-TSC1 structures, one TBC1D7 molecule was able to interact simultaneously with two TSC1 coiled-coil fragments, and alignment of these domains highlights structural similarity.
“In both cases, one TBC1D7 molecule was able to interact simultaneously with two TSC1 coiled-coil fragments, and alignment of these domains highlights structural similarity (Fig. 5G).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Qin et al., 2016
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Nielipinska, D., Orlikowska, M., Nielipinski, M., Sekula, B., Błażewska, K. M., Gendaszewska‐Darmach, E., & Pietrzyk‐Brzezinska, A. J. (2026) · Protein Science · doi:10.1002/pro.70581
- Authors
- Qin, J., Wang, Z., Hoogeveen-Westerveld, M., Shen, G., Gong, W., Nellist, M., & Xu, W.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Washington (US)
- University of Science and Technology of China (CN)
- Erasmus MC (NL)
- Corresponding author
- Gong, Weimin
- Nellist, Mark
- Xu, Wenqing
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 291
- Issue
- 16
- Pages
- 8591-8601
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4861430
- OpenAlex
- W2284424749
- Cited by
- 37
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 2
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Chinese Academy of Sciences (XDB08010303)
- Congressionally Directed Medical Research Programs (W81XWH-13-1-0059 (TS120073))
- 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, TSC1, protein-protein interaction, coiled-coil domain, crystal structure, mTORC1 signaling, TSC1/TSC2 complex, intellectual disability, hydrophobic interface
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Carrier Proteins, Humans, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Protein Structure, Quaternary, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins
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