Two binding partners cooperate to activate the molecular motor Kinesin-1

Blasius, T. Lynne; Cai, Dawen; Jih, Gloria; Toret, Christopher P.; Verhey, Kristen J.

doi:10.1083/jcb.200605099

Cited by 210 publications

(298 citation statements)

References 30 publications

(61 reference statements)

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“…As reported, FEZ1 coprecipitates with Kinesin-1 (KIF5C) (Fig. S3B, lane 1) (18). In triple transfections with FEZ1, KIF5C, and either Munc18 or Stx, immunoprecipitation of FEZ1 resulted in efficient coprecipitation of either set of proteins, demonstrating that FEZ1 indeed functions as a kinesin adaptor for Munc18 and Stx (Fig.…”

Section: Fez1mentioning

confidence: 54%

See 1 more Smart Citation

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylationdeficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases. T he formation and maintenance of presynaptic boutons are intricate but highly efficient processes during which the machinery for exocytosis and recycling of synaptic vesicles is assembled from preformed units. These units are delivered to the nascent synapse via molecular motor proteins of the kinesin superfamily (reviewed in Ref. 1).Although Kinesin-3 appears to be the main motor transporting synaptic vesicle precursors, recent evidence suggests that Kinesin-1 (KIF5) is also involved. In Drosophila, deletion of UNC-76/ fasciculation and elongation protein zeta 1 (FEZ1), a specific adaptor for Kinesin-1, left synaptic vesicles stranded in the axon (2, 3), showing that Kinesin-1 is needed at least during later phases of axonal transport. Transport of the synaptic vesicle protein synaptotagmin by the UNC-76/Kinesin-1 complex requires phosphorylation of UNC-76 by the UNC-51/ATG1 kinase, a prerequisite for UNC-76 to bind synaptotagmin (3). Deletion of this kinase phenocopies deletion of UNC-76. Indeed, phosphorylation-regulated interactions between cargo, adaptors, and kinesins have also been observed for other transport complexes such as the kinesin light chain/JIP1 (c-Jun N-terminal kinase-interacting protein 1) complex (4). This suggests that phosphorylation is a common mechanism for the regulation of kinesin-based transport complexes (5).Less is known about the involvement of Kinesin-1 in the transport of other classes of synaptic precursor vesicles. Transport of syntaxin 1a (Stx), an essential component of the exocytotic release apparatus residing in the presynaptic plasma membrane, is clearly distinct from synaptic vesicle precursors and appears to involve a complex between Kinesin-1 and the Stx-binding protein syntabulin (6, 7). Down-regulation or expression of dominant-negative syntabulin reduces but does not abolish membrane delivery of Stx, indicating the existence of other transport mechanisms (6). Moreover, proper intracellular trafficking of Stx and its function in exocytosis depends on Munc18 coexpression (8-14). Stx tra...

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Section: Fez1mentioning

confidence: 54%

“…FEZ1 binds Kinesin-1 and is involved in synaptic vesicle transport (2,3,18). We wondered whether FEZ1 might also similarly transport Stx and/or Munc18.…”

Section: Fez1mentioning

confidence: 99%

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Chua

Butkevich

Worseck

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Future studies of other regimes are still needed to completely understand and recapitulate intracellular cargo transport. For instance, both myosin-V and kinesin-1 can fold up and autoinhibit (25)(26)(27)(28). It is unknown how such regulation would affect unidirectional and bidirectional cargo transport.…”

Section: Discussionmentioning

confidence: 99%

Motor transport of self-assembled cargos in crowded environments

Conway¹,

Wood

Tüzel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular transport of cargo particles is performed by multiple motors working in concert. However, the mechanism of motor association to cargos is unknown. It is also unknown how long individual motors stay attached, how many are active, and how multimotor cargos would navigate a densely crowded filament with many other motors. Prior theoretical and experimental biophysical model systems of intracellular cargo have assumed fixed teams of motors transporting along bare microtubules or microtubules with fixed obstacles. Here, we investigate a regime of cargos transporting along microtubules crowded with free motors. Furthermore, we use cargos that are able to associate or dissociate motors as it translocates. We perform in vitro motility reconstitution experiments with high-resolution particle tracking. Our model system consists of a quantum dot cargo attached to kinesin motors, and additional free kinesin motors that act as traffic along the microtubule. Although high densities of kinesin motors hinder forward motion, resulting in a lower velocity, the ability to associate motors appears to enhance the run length and attachment time of the quantum dot, improving overall cargo transport. These results suggest that cargos that can associate new motors as they transport could overcome traffic jams.axonal transport | cytoplasmic dynein

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“…206 The latter observation is consistent with demonstrations of an involvement of FEZ1 in kinesin-based motility. 207 When the proteins are overexpressed, DISC1 binds robustly to FEZ1, and these proteins colocalize in growth cones of cultured rat hippocampal neurons. 76 The interaction is upregulated during differentiation of rat PC12 cells, and differentiated PC12 cells overexpressing DISC1 exhibit enhanced neurite production, which involves DISC1/FEZ1 complexes.…”

Section: Disc1 Interaction With Fez1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Two binding partners cooperate to activate the molecular motor Kinesin-1

Cited by 210 publications

References 30 publications

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Motor transport of self-assembled cargos in crowded environments

The DISC locus in psychiatric illness

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