title: Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.
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.
authors.affiliation: Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Ye Julia
authors.initials: YJ
authors.lastname: Zhu
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhong
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.forename: Weimin
authors.initials: W
authors.lastname: Gong
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D029702:Schizosaccharomyces pombe Proteins; C000624650:TSC1 protein, human; C471572:Tsc1 protein, S pombe; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins