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Structural basis for activation of the titin kinase domain during myofibrillogenesis

Author

Listed:
  • Olga Mayans

    (European Molecular Biology Laboratory)

  • Peter F. M. van der Ven

    (University of Potsdam)

  • Matthias Wilm

    (European Molecular Biology Laboratory Heidelberg)

  • Alexander Mues

    (European Molecular Biology Laboratory Heidelberg)

  • Paul Young

    (European Molecular Biology Laboratory Heidelberg)

  • Dieter O. Fürst

    (University of Potsdam)

  • Matthias Wilmanns

    (European Molecular Biology Laboratory)

  • Mathias Gautel

    (European Molecular Biology Laboratory Heidelberg)

Abstract

The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. Here we present the crystal structure of titin's only catalytic domain, an autoregulated serine kinase (titin kinase). The structure shows how the active site is inhibited by a tyrosine of the kinase domain. We describe a dual mechanism of activation of titin kinase that consists of phosphorylation of this tyrosine and binding of calcium/calmodulin to the regulatory tail. The serine kinase domain of titin is the first known non-arginine–aspartate kinase to be activated by phosphorylation. The phosphorylated tyrosine is not located in the activation segment, as in other kinases, but in the P+ 1 loop, indicating that this tyrosine is a binding partner of the titinkinase substrate. Titin kinase phosphorylates the muscle protein telethonin in early differentiating myocytes, indicating that this kinase may act in myofibrillogenesis.

Suggested Citation

  • Olga Mayans & Peter F. M. van der Ven & Matthias Wilm & Alexander Mues & Paul Young & Dieter O. Fürst & Matthias Wilmanns & Mathias Gautel, 1998. "Structural basis for activation of the titin kinase domain during myofibrillogenesis," Nature, Nature, vol. 395(6705), pages 863-869, October.
    • Handle: RePEc:nat:nature:v:395:y:1998:i:6705:d:10.1038_27603
    DOI: 10.1038/27603
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