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The DCX-domain tandems of doublecortin and doublecortin-like kinase

Nature Structural Biology volume 10, pages 324333 (2003) | Download Citation

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Abstract

The doublecortin-like domains (DCX), which typically occur in tandem, are novel microtubule-binding modules. DCX tandems are found in doublecortin, a 360-residue protein expressed in migrating neurons; the doublecortin-like kinase (DCLK); the product of the RP1 gene that is responsible for a form of inherited blindness; and several other proteins. Mutations in the gene encoding doublecortin cause lissencephaly in males and the 'double-cortex syndrome' in females. We here report a solution structure of the N-terminal DCX domain of human doublecortin and a 1.5 Å resolution crystal structure of the equivalent domain from human DCLK. Both show a stable, ubiquitin-like tertiary fold with distinct structural similarities to GTPase-binding domains. We also show that the C-terminal DCX domains of both proteins are only partially folded. In functional assays, the N-terminal DCX domain of doublecortin binds only to assembled microtubules, whereas the C-terminal domain binds to both microtubules and unpolymerized tubulin.

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Acknowledgements

This research is supported by NIH grants to Z.S.D. and to C.A.W. A NATO Collaborative Link grant to Z.S.D. and J.O. is gratefully acknowledged. T.C. and D.K. are recipients of the Young Scholar Awards from the Foundation for Polish Science. J.O. is an International Scholar of the Howard Hughes Medical Institute. J.H.B. is supported by grants from the NIH and the Leukemia and Lymphoma Society. We thank N. Olekhnovich for excellent technical assistance, F. Abildgaard of NMRFAM for assistance with the collection of some of the NMR data, P. Sheffield for his contribution in the early phase of the project, A.V. Somlyo for helpful comments on the manuscript and L. Tamm for assistance with the tubulin polymerization experiments.

Author information

Author notes

    • Myung Hee Kim
    • , Tomasz Cierpicki
    •  & Urszula Derewenda

    The contributions of these authors were particularly important to this study.

Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908-0736, USA.

    • Myung Hee Kim
    • , Tomasz Cierpicki
    • , Urszula Derewenda
    • , Yancho Devedjiev
    • , Jacek Otlewski
    • , John H. Bushweller
    •  & Zygmunt S. Derewenda
  2. Laboratory of Protein Engineering, Institute of Biochemistry & Molecular Biology, University of Wroclaw, Tamka 2, 50-137 Wroclaw, Poland.

    • Tomasz Cierpicki
    • , Daniel Krowarsch
    •  & Jacek Otlewski
  3. Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.

    • Yuanyi Feng
    •  & Christopher A. Walsh
  4. Synchrotron Radiation Research Section, Macromolecular Crystallography Laboratory, NCI, Brookhaven National Laboratory, Upton, New York 11973, USA.

    • Zbigniew Dauter

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to John H. Bushweller or Zygmunt S. Derewenda.

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DOI

https://doi.org/10.1038/nsb918

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