Nature Structural Biology10, 324 - 333 (2003)
Published online: 14 April 2003; | doi:10.1038/nsb918
The DCX-domain tandems of doublecortin and doublecortin-like kinase
Myung Hee Kim1, 2, Tomasz Cierpicki1, 2, 3, Urszula Derewenda1, 2, Daniel Krowarsch3, Yuanyi Feng4, Yancho Devedjiev2, Zbigniew Dauter5, Christopher A. Walsh4, Jacek Otlewski2, 3, John H. Bushweller2
& Zygmunt S. Derewenda2
1
The contributions of these authors were particularly important to this study.
2
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908-0736, USA.
3
Laboratory of Protein Engineering, Institute of Biochemistry & Molecular Biology, University of Wroclaw, Tamka 2, 50-137 Wroclaw, Poland.
4
Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
5
Synchrotron Radiation Research Section, Macromolecular Crystallography Laboratory, NCI, Brookhaven National Laboratory, Upton, New York 11973, USA.
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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