1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate

  1. Qi Wang
  2. Erik M Vogan
  3. Laura M Nocka
  4. Connor E Rosen
  5. Julie A Zorn
  6. Stephen C Harrison
  7. John Kuriyan  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Berkeley, United States
  2. Beryllium Inc, United States
  3. University of California, Berkeley, United States
  4. Harvard Medical School, Howard Hughes Medical Institute, United States
Research Article
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Cite this article as: eLife 2015;4:e06074 doi: 10.7554/eLife.06074

Abstract

Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

Article and author information

Author details

  1. Qi Wang

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Erik M Vogan

    Beryllium Inc, Boston, United States
    Competing interests
    No competing interests declared.
  3. Laura M Nocka

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Connor E Rosen

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Julie A Zorn

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Stephen C Harrison

    Laboratory of Molecular Medicine, Harvard Medical School, Howard Hughes Medical Institute, Boston, United States
    Competing interests
    Stephen C Harrison, Reviewing editor, eLife.
  7. John Kuriyan

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    jkuriyan@mac.com
    Competing interests
    John Kuriyan, Senior editor, eLife.

Reviewing Editor

  1. Philip A Cole, Johns Hopkins University School of Medicine, USA

Publication history

  1. Received: December 13, 2014
  2. Accepted: February 19, 2015
  3. Accepted Manuscript published: February 20, 2015 (version 1)
  4. Version of Record published: April 2, 2015 (version 2)

Copyright

© 2015, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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