Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations
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Tuberous sclerosis complex is a disease caused by mutations in two tumor-suppressor genes, TSC1 and TSC2. The TSC1 protein, also known as hamartin, has a critical role in controlling mTOR signalling. TSC1 does not bear apparent sequence homology with other proteins. Here we show that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved. The crystal structure of this yeast TSC1 core domain shows that it contains a pseudo-HEAT repeat fold with its C-terminal end capped by a helical subdomain. This allows us to model the three-dimensional structure of the human TSC1 N-terminal domain (TSC1-NTD), which anchors essentially all pathogenic TSC1 missense mutations found in tuberous sclerosis patients. Interestingly, most pathogenic mutations map inside of the folded TSC1-NTD structure, whereas most non-pathogenic variants are on the structural surface. This indicates that the disruption of the TSC1-NTD globular structure is a major cause of tuberous sclerosis.
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The N-terminal core domain of S. pombe TSC1 is exclusively α-helical, as predicted by bioinformatic analyses, and forms a solenoid built of HEAT repeats.
“These authors found that the core domain is exclusively α-helical, as predicted by bioinformatic analyses, and forms a solenoid built of HEAT repeats.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sun et al., 2013
In one crystal form of the S. pombe TSC1 core domain, ten monomers form two juxtaposed pentameric rings, ultimately forming a face-to-face decamer.
“In one crystal form, ten monomers form two juxtaposed pentameric rings, ultimately forming a ‘face-to-face’ decamer (Fig. 5B).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sun et al., 2013
The driver for the TSC1 core domain assembly appears to be an overhanging helix from each core domain, which makes contacts with neighboring domains.
“The driver for such an assembly appears to be an overhanging helix from each core domain, which makes contacts with neighboring domains.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sun et al., 2013
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References 47 · Cited by 27
- Authors
- Sun, W., Zhu, Y. J., Wang, Z., Zhong, Q., Gao, F., Lou, J., Gong, W., & Xu, W.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Washington (US)
- Corresponding author
- Gong, Weimin
- Xu, Wenqing
- Venue
- Nature Communications
- Published
- 2013-07-16
- Volume
- 4
- Issue
- 1
- Pages
- 2135-2135
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2143597735
- Cited by
- 27
- References
- 47
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 2
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- tuberous sclerosis complex, TSC1, hamartin, mTOR signaling, missense mutations, pathogenic variants, protein structure, tumor suppressor
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Schizosaccharomyces, Tuberous Sclerosis, Conserved Sequence, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Tumor Suppressor Proteins, Schizosaccharomyces pombe Proteins
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