IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v4y2013i1d10.1038_ncomms3135.html
   My bibliography  Save this article

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

Author

Listed:
  • Wei Sun

    (Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences
    University of Washington)

  • Ye Julia Zhu

    (University of Washington)

  • Zhizhi Wang

    (University of Washington)

  • Qiang Zhong

    (Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences)

  • Feng Gao

    (Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences)

  • Jizhong Lou

    (Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences)

  • Weimin Gong

    (Beijing Key Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences)

  • Wenqing Xu

    (University of Washington)

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.

Suggested Citation

  • Wei Sun & Ye Julia Zhu & Zhizhi Wang & Qiang Zhong & Feng Gao & Jizhong Lou & Weimin Gong & Wenqing Xu, 2013. "Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations," Nature Communications, Nature, vol. 4(1), pages 1-8, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3135
    DOI: 10.1038/ncomms3135
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms3135
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms3135?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3135. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.