4KK1

Crystal Structure of TSC1 core domain from S. pombe

Summary for 4KK1

• Entry DOI: 10.2210/pdb4kk1/pdb
• Related: 4KK0
• Descriptor: Tuberous sclerosis 1 protein homolog (1 entity in total)
• Functional Keywords: heat repeat, tumor suppressor, immune system
• Biological source: Schizosaccharomyces pombe (Fission yeast)
• Cellular location: Cytoplasm: Q09778
• Total number of polymer chains: 20
• Total formula weight: 1012808.12

Authors

Sun, W.,Zhu, Y.,Wang, Z.Z.,Zhong, Q.,Gao, F.,Lou, J.Z.,Gong, W.M.,Xu, W.Q. (deposition date: 2013-05-05, release date: 2013-07-17, Last modification date: 2024-10-16)

Primary citation

Sun, W.,Zhu, Y.J.,Wang, Z.,Zhong, Q.,Gao, F.,Lou, J.,Gong, W.,Xu, W.
Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.
Nat Commun, 4:2135-2135, 2013

PubMed Abstract: 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.

PubMed: 23857276
DOI: 10.1038/ncomms3135

Experimental method

X-RAY DIFFRACTION (3.3 Å)