4kk0

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Crystal Structure of TSC1 core domain from S. pombe

Structural highlights

4kk0 is a 10 chain structure with sequence from Schizosaccharomyces pombe 972h-. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Ligands:MSE
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TSC1_SCHPO Together with tsc2, required for uptake of various amino-acids from the environment and for proper conjugation. Involved in induction of gene expression of permeases and genes required for meiosis upon nitrogen starvation. May act as a GTPase-activating protein (GAP) for the small GTPase rhb1.[1] [2] [3]

Publication Abstract from PubMed

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.

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.,Sun W, Zhu YJ, Wang Z, Zhong Q, Gao F, Lou J, Gong W, Xu W Nat Commun. 2013 Jul 16;4:2135. doi: 10.1038/ncomms3135. PMID:23857276[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Matsumoto S, Bandyopadhyay A, Kwiatkowski DJ, Maitra U, Matsumoto T. Role of the Tsc1-Tsc2 complex in signaling and transport across the cell membrane in the fission yeast Schizosaccharomyces pombe. Genetics. 2002 Jul;161(3):1053-63. PMID:12136010
  2. ↑ van Slegtenhorst M, Carr E, Stoyanova R, Kruger WD, Henske EP. Tsc1+ and tsc2+ regulate arginine uptake and metabolism in Schizosaccharomyces pombe. J Biol Chem. 2004 Mar 26;279(13):12706-13. Epub 2004 Jan 12. PMID:14718525 doi:10.1074/jbc.M313874200
  3. ↑ Nakase Y, Fukuda K, Chikashige Y, Tsutsumi C, Morita D, Kawamoto S, Ohnuki M, Hiraoka Y, Matsumoto T. A defect in protein farnesylation suppresses a loss of Schizosaccharomyces pombe tsc2+, a homolog of the human gene predisposing to tuberous sclerosis complex. Genetics. 2006 Jun;173(2):569-78. Epub 2006 Apr 19. PMID:16624901 doi:10.1534/genetics.106.056895
  4. ↑ Sun W, Zhu YJ, 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. 2013 Jul 16;4:2135. doi: 10.1038/ncomms3135. PMID:23857276 doi:10.1038/ncomms3135

Contents


PDB ID 4kk0

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