The Mitosis and Neurodevelopment Proteins NDE1 and NDEL1 Form Dimers, Tetramers, and Polymers with a Folded Back Structure in Solution

Soares, Dinesh C.; Bradshaw, Nicholas J.; Zou, Juan; Kennaway, Christopher K.; Hamilton, Russell S.; Chen, Zhuo A.; Wear, Martin A.; Blackburn, Elizabeth A.; Bramham, Janice; Böttcher, Bettina; Millar, J. Kirsty; Barlow, Paul N.; Walkinshaw, Malcolm D.; Rappsilber, Juri; Porteous, David J.

doi:10.1074/jbc.m112.393439

Cited by 41 publications

(57 citation statements)

References 54 publications

(141 reference statements)

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“…NDE1 is thought to fold into a hairpin that brings the dynein binding sites at the N- and C-terminus in close proximity so as to function as one contiguous binding site. Furthermore, it is thought that NDE1 can form dimers and tetramers (22). Given that EGFP can dimerize on its own, perhaps this interfered with the normal folding or dimerization of NDE1.…”

Section: Resultsmentioning

confidence: 99%

“…Dynein is known to form two different complexes, one with NDE1 (Nuclear distribution E; NUD-E) / Lis1 (Lissencephaly 1) (22) and the other with dynactin, a multisubunit complex whose largest subunit is p150 Glued (23). We hypothesized that these two different dynein complexes were responsible for different aspects of the secretory process, one for MTOC translocation and the other for vesicle movements.…”

Section: Introductionmentioning

confidence: 99%

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Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

Nath

Christian

Tan

et al. 2016

The Journal of Immunology

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Helper and cytotoxic T cells accomplish focused secretion through the clustering of vesicles around the MTOC and translocation of the MTOC to the target contact site. Here, using Jurkat cells and OT-I T cell receptor (TcR) transgenic primary murine CTLs, we show that the dynein-binding proteins NDE1 and dynactin (as represented by p150Glued) form mutually exclusive complexes with dynein, exhibit non-overlapping distributions in target-stimulated cells, and mediate different transport events. When Jurkat cells expressing a dominant negative form of NDE1 (NDE1-EGFP fusion) were activated by SEE-coated Raji cells, NDE1 and dynein failed to accumulate at the immunological synapse (IS) and MTOC translocation was inhibited. Knockdown of NDE1 in Jurkat cells or primary mouse CTLs also inhibited MTOC translocation and CTL-mediated killing. In contrast to NDE1, knockdown of p150Glued, which depleted the alternative dynein-dynactin complex, resulted in impaired accumulation of CTLA-4 and granzyme-B containing intracellular vesicles at the IS, while MTOC translocation was not affected. Depletion of p150Glued in CTLs also inhibited CTL-mediated lysis. We conclude that the NDE1/Lis1 and dynactin complexes separately mediate two key components of T cell focused secretion, namely translocation of the MTOC and lytic granules to the IS, respectively.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

Nath

Christian

Tan

et al. 2016

The Journal of Immunology

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“…NDE1 exon 7 is located C-terminalα-helix where many phosphorylation sites are located (figures 1A and 1B), and predicted to regulate the NDE1 structure and interactions with other proteins. 31,49 Moreover, it was suggested disease associated mutations cluster within protein interacting domains. 50 In the current study, we could detect a significant association (OR = 7.1, P = .039) between SCZ and S214F in the sample comprising 8734 Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Third, we could not perform structural analysis of S214F and R234C because these mutations are located at the C-terminal region, an area known to be difficult to predict the structure of. 49,58 Future studies should focus on the structural effect of the mutations discovered in this study.…”

Section: Discussionmentioning

confidence: 99%

Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

Kimura

Tsuboi

Wang

et al. 2014

Schizophrenia Bulletin

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Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ≤5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

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“…The head domain is predicted to be largely disordered (Soares et al . ), implying a structural flexibility that could facilitate binding to multiple targets. On the contrary, the C‐terminal tail domain (approximately amino acids 350–854 in human DISC1) is well conserved across species and predicted to be highly structured, consisting of a series of α‐helices interspersed with at least four regions comprising strong coiled‐coil forming potential (Soares et al .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the role of DISC1 in synaptic plasticity

Tropea

Hardingham

Millar

et al. 2018

The Journal of Physiology

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Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self‐association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N‐terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element‐binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal‐7) and Rac1. C‐terminal directed mutations also impair plasticity possibly through altered interactions with lissencephaly protein 1 (LIS1) and nuclear distribution protein nudE‐like 1 (NDEL1), thereby affecting developmental processes such as dendritic structure and spine maturation. Many of the same molecules involved in DISC1's cytoskeletal interactions are also involved in intracellular trafficking, raising the possibility that impairments in intracellular trafficking affect cytoskeletal development and vice versa. While the multiplicity of DISC1 protein interactions makes it difficult to pinpoint a single causal signalling pathway, we suggest that the immediate‐term effects of N‐terminal influences on GluA1, Rac1 and CREB, coupled with the developmental effects of C‐terminal influences on trafficking and the cytoskeleton make up the two main branches of DISC1's effect on synaptic plasticity and dendritic spine stability.

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The Mitosis and Neurodevelopment Proteins NDE1 and NDEL1 Form Dimers, Tetramers, and Polymers with a Folded Back Structure in Solution

Cited by 41 publications

References 54 publications

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion

Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility

Mechanisms underlying the role of DISC1 in synaptic plasticity

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