title: The DCX-domain tandems of doublecortin and doublecortin-like kinase.
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 A 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.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908-0736, USA.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Kim
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Urszula
authors.initials: U
authors.lastname: Derewenda
authors.forename: Daniel
authors.initials: D
authors.lastname: Krowarsch
authors.forename: Yuanyi
authors.initials: Y
authors.lastname: Feng
authors.forename: Yancho
authors.initials: Y
authors.lastname: Devedjiev
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Dauter
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Jacek
authors.initials: J
authors.lastname: Otlewski
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
authors.forename: Zygmunt S
authors.initials: ZS
authors.lastname: Derewenda
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001921:Brain / Q000002:abnormalities; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry*; D017124:Conserved Sequence; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D000089742:Doublecortin-Like Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009479:Neuropeptides / Q000737:chemistry*; D010750:Phosphoproteins / Q000737:chemistry; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010750:Phosphoproteins; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases