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.
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Kim, M., Cierpicki, T., Derewenda, U. et al. The DCX-domain tandems of doublecortin and doublecortin-like kinase. Nat Struct Mol Biol 10, 324–333 (2003). https://doi.org/10.1038/nsb918
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DOI: https://doi.org/10.1038/nsb918
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