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

Kim, Myung Hee; Cierpicki, Tomasz; Derewenda, Urszula; Krowarsch, Daniel; Feng, Yuanyi; Devedjiev, Y.; Dauter, Zbigniew; Walsh, Christopher A.; Otlewski, Jacek; Bushweller, John H.; Derewenda, Zygmunt S.

doi:10.1038/nsb918

Cited by 125 publications

(175 citation statements)

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“…A cell expressing GFP-Dcx WT and FLAG-neurabin II (4 -6) stained with phalloidin-TRITC (5, red) showed partial co-localization of GFP-Dcx WT and actin. In a cell expressing GFP-Dcx WT and FLAG-neurabin II (7)(8)(9), partial co-localization of GFP-Dcx WT (7) with whirls of microtubules (8, red) was observed. 10 -18, in a cell expressing GFP-Dcx S47E and FLAG-neurabin II (10 -12), GFP-Dcx S47E (10) is highly co-localized with FLAG-neurabin II (11, superimposed image is shown in 12).…”

Section: Fig 2 F-actin-bundling Activity Of DCXmentioning

confidence: 99%

“…4C, 16 -18). The GFP-Dcx S297E muta- (1)(2)(3)(4)(5)(6) or GFP-Dcx S47E (7)(8)(9)(10)(11)(12). Fixed cells were stained either with a mouse anti-tubulin antibody visualized with TRITC-conjugated anti-mouse antibody (2,8) or with phalloidin to reveal actin filaments (5,11).…”

Section: Fig 2 F-actin-bundling Activity Of DCXmentioning

confidence: 99%

“…Structure-function studies have shown that the first DCX domain binds to microtubules, whereas the second one binds to microtubules and to unpolymerized tubulin (8). In conjunction with the well characterized DCX function as a microtubule-polymerizing, -stabilizing, and -bundling protein (6, 9 -11), it is thought that the second DCX domain brings tubulin dimers to the growing tips of the microtubules to accelerate microtubule growth, and microtubules are stabilized or bundled when both domains bind to microtubules.…”

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confidence: 99%

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Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Tsukada

Prokscha

Ungewickell

et al. 2005

Journal of Biological Chemistry

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Mutations in the human Doublecortin (DCX) gene cause X-linked lissencephaly, a neuronal migration disorder affecting the neocortex and characterized by mental retardation and epilepsy. Because dynamic cellular asymmetries such as those seen in cell migration critically depend on a cooperation between the microtubule and actin cytoskeletal filament systems, we investigated whether Dcx, a microtubule-associated protein, is engaged in cytoskeletal cross-talk. We now demonstrate that Dcx co-sediments with actin filaments (F-actin), and using light and electron microscopy and spin down assays, we show that Dcx induces bundling and crosslinking of microtubules and F-actin in vitro. It has recently been shown that binding of Dcx to microtubules is negatively regulated by phosphorylation of the Dcx at Ser-47 or Ser-297. Although the phosphomimetic green fluorescent protein (GFP)-Dcx S47E transfected into COS-7 cells had a reduced affinity for microtubules, we found that pseudophosphorylation was not sufficient to cause Dcx to bind to F-actin. When cells were co-transfected with neurabin II, a protein that binds F-actin as well as Dcx, GFP-Dcx and to an even greater extent GFP-Dcx S47E became predominantly associated with filamentous actin. Thus Dcx phosphorylation and neurabin II combinatorially enhance Dcx binding to F-actin. Our findings raise the possibility that Dcx acts as a molecular link between microtubule and actin cytoskeletal filaments that is regulated by phosphorylation and neurabin II.

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Section: Fig 2 F-actin-bundling Activity Of DCXmentioning

confidence: 99%

Section: Fig 2 F-actin-bundling Activity Of DCXmentioning

confidence: 99%

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Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Tsukada

Prokscha

Ungewickell

et al. 2005

Journal of Biological Chemistry

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“…13 Recently, an additional member of this protein family, doublecortin kinase 2, has been described, and found to posses MT binding activities. 14 The structure of the DCX domain is a ubiquitin-like fold, 15 different from that of classical MAPs. DCX is embedded in fenestrations localized between protofilaments from which MTs are built.…”

Section: Introductionmentioning

confidence: 99%

The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily

Coquelle¹,

Levy²,

Bergmann³

et al. 2006

Cell Cycle

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The doublecortin-like (DCX) domains serve as protein-interaction platforms. DCX tandem domains appear in the product of the X-linked doublecortin (DCX) gene, in retinitis pigmentosa-1 (RP1), as well as in other gene products. Mutations in the human DCX gene are associated with abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, while DCDC2 has been associated with dyslectic reading disabilities. Motivated by the possible importance of this gene family, a thorough analysis to detect all family members in the mouse was conducted. The DCX-repeat gene superfamily is composed of eleven paralogs, and we cloned the DCX domains from nine different genes. Our study questioned which functions attributed to the DCX domain, are conserved among the different members. Our results suggest that the proteins with the DCX-domain have conserved and unique roles in microtubule regulation and signal transduction. All the tested proteins stimulated microtubule assembly in vitro. Proteins with tandem repeats stabilized the microtubule cytoskeleton in transfected cells, while those with single repeats localized to actin-rich subcellular structures, or the nucleus. All tested proteins interacted with components of the JNK/MAP-kinase pathway, while only a subset interacted with Neurabin 2, and a nonoverlapping group demonstrated actin association. The sub-specialization of some members due to confined intracellular localization, and protein interactions may explain the success of this superfamily.

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“…The partial p25alpha domain, a 30-32 aa long sequence, occurs independently from the other parts of the p25alpha domain as well, mostly but not exclusively in protists (Orosz 2012). The function of apicortins is unknown; however, both the p25alpha and DCX domains play an important role in the stabilization of microtubules (Hlavanda et al 2002;Tirián et al 2003;Sapir et al 2000;Kim et al 2003), which suggests a similar role for apicortin. Apicortin received its name on the basis of its occurrence (Apicomplexa) and one of its characteristic domains (doublecortin).…”

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Wider than Thought Phylogenetic Occurrence of Apicortin, A Characteristic Protein of Apicomplexan Parasites

Orosz

2016

J Mol Evol

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

Cited by 125 publications

References 53 publications

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

Doublecortin Association with Actin Filaments Is Regulated by Neurabin II

The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily

Wider than Thought Phylogenetic Occurrence of Apicortin, A Characteristic Protein of Apicomplexan Parasites

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