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J. Biol. Chem., Vol. 275, Issue 44, 34442-34450, November 3, 2000
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From the Doublecortin (DCX) missense mutations are found
in two clusters in patients with defective cortical neuronal migration.
Although DCX can function as a microtubule-associated protein (MAP),
the potential relationship between its MAP activity and neuronal
migration is not understood. Here we show that the two clusters of
patient mutations precisely define an internal tandem repeat. Each
repeat alone binds tubulin, whereas neither repeat is sufficient for co-assembly with microtubules. The two tandem repeats are sufficient to
mediate microtubule polymerization, and representative patient missense
mutations lead to impaired polymerization both in vitro and
in vivo as well as impaired microtubule stabilization.
Furthermore, each repeat is predicted to have the secondary structure
of a
Patient Mutations in Doublecortin Define a Repeated
Tubulin-binding Domain*
,,
Division Pediatric Neurology, Department of
Neurosciences, Biomedical Sciences Graduate Program, University of
California, San Diego, La Jolla, California 92093, the
§ Protein Machine Group, Department of Molecular Biology,
DNAX Research Institute, Palo Alto, California 94304, and the
¶ Division of Neurogenetics, Department of Neurology, Beth Israel
Deaconess Medical Center, Harvard Medical School,
Boston, Massachusetts 02115
-grasp superfold motif, a motif not found in other MAPs. The patient mutations are predicted to disrupt the structure of the motif,
suggesting that the motif may be critical for the DCX-tubulin interaction. These data provide both genetic and biochemical evidence that the interaction of DCX with microtubules is dependent upon this
novel repeated tubulin-binding motif.
*
This work was supported by National Institutes of
Health Grants RO1 NS 38097 and PO1 NS39404 (to C. A. W.), by
NINDS Neurological Sciences Academic Development Award 5K12NS01701-05,
by the Department of Neurosciences at the University of California, San
Diego, by a Junior Investigator Grant from the Epilepsy Foundation, and by funds from the Searle Scholars Program (to J. G. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: MTF 324, 9500 Gilman Dr., La Jolla, CA 92093-0624. Tel.: 858-822-3535; Fax:
858-534-1437; E-mail: jogleeson@ucsd.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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