Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The light chains (KLCs) of the heterotetrameric microtubule motor kinesin-1, that bind to cargo adaptor proteins and regulate its activity, have a capacity to recognize short peptides via their tetratricopeptide repeat domains (KLC^TPR). Here, using X-ray crystallography, we show how kinesin-1 recognizes a novel class of adaptor motifs that we call 'Y-acidic' (tyrosine flanked by acidic residues), in a KLC-isoform-specific manner. Binding specificities of Y-acidic motifs (present in JIP1 and in TorsinA) to KLC1^TPR are distinct from those utilized for the recognition of W-acidic motifs, found in adaptors, that are KLC-isoform non-selective. However, a partial overlap on their receptor-binding sites implies that adaptors relying on Y-acidic and W-acidic motifs must act independently. We propose a model to explain why these two classes of motifs that bind to the concave surface of KLC^TPR with similar low micromolar affinity can exhibit different capacities to promote kinesin-1 activity.
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PMID:Structural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors. 3032 May 53

Kinesins are essential for the transport and positioning of several biomolecules through moving along the microtubule in eukaryotic cells. Up to now, there are 14 kinesin family proteins known. The MAPK pathway which is composed of multiple proteins constituting a complex cascade also plays important roles in cell proliferation, differentiation and apoptosis in eukaryotic cells. MAPK pathway includes three main kinases: MAPK Kinase Kinase, MAPK Kinase and mitogen-activated protein kinase that activate and phosphorylate downstream step by step in which abundant proteins scaffold together in complex ways. To accomplish the transmission of a variety of signals, numbers of kinesins are closely associated with the MAPK cascade such as Kinesin-1, Kinesin-3, Kinesin-5, Kinesin-8, Kinesin-11 and Kinesin-13 families in mammals and two kinds of kinesin-like proteins in plants. Studies have indicated that Kinesin-1 light chain KLC1, Kinesin-1 heavy chain KIF5B and Kinesin-11 family motor KIF26B interact with extracellular signal-regulated kinase ERK closely to regulate neuronal differentiation and mediate the chemosensitivity of osteosarcoma cells to drugs, Kinesin-3 family motor KIF13B and Kinesin-5 family motor Eg5 perform functions in regulating p38 to regulate the myelination of nervous system and facilitate the spindle elongation and tension, Kinesin-8 family motor MS-KIF18A and three isoforms of kinesin-13 can also connect and interact with MAPK pathway to transport estrogen receptor to the nucleus and control cell migration. In plant cells, NPK1-activating kinesin-like protein 1 NACK and AtNACK1 (HIK) kinesin-like protein HINKEL are two members of the plant-specific kinesin-7. They function as Ras at the upstream of MAPK pathway to regulate cytokinesis. This review summarizes the novel roles of kinesins in MAPK cascade and tries to discuss the mechanism of the interaction between them using mammalian and plant cells as models.
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PMID:Kinesins in MAPK cascade: How kinesin motors are involved in the MAPK pathway? 3034 67

Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer's disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer's disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer's disease.
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PMID:LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer's disease brains. 3106 17

Damage to axonal transport is an early pathogenic event in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer's disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer's disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer's disease.
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PMID:Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer's disease and regulates axonal transport and processing of the amyloid precursor protein. 3180 24

Mitochondria change distribution across cells following a variety of pathophysiological stimuli. The mechanisms presiding over this redistribution are yet undefined. In a murine model overexpressing Drp1 specifically in skeletal muscle, we find marked mitochondria repositioning in muscle fibres and we demonstrate that Drp1 is involved in this process. Drp1 binds KLC1 and enhances microtubule-dependent transport of mitochondria. Drp1-KLC1 coupling triggers the displacement of KIF5B from kinesin-1 complex increasing its binding to microtubule tracks and mitochondrial transport. High levels of Drp1 exacerbate this mechanism leading to the repositioning of mitochondria closer to nuclei. The reduction of Drp1 levels decreases kinesin-1 activation and induces the partial recovery of mitochondrial distribution. Drp1 overexpression is also associated with higher cyclin-dependent kinase-1 (Cdk-1) activation that promotes the persistent phosphorylation of desmin at Ser-31 and its disassembling. Fission inhibition has a positive effect on desmin Ser-31 phosphorylation, regardless of Cdk-1 activation, suggesting that induction of both fission and Cdk-1 are required for desmin collapse. This altered desmin architecture impairs mechanotransduction and compromises mitochondrial network stability priming mitochondria transport through microtubule-dependent trafficking with a mechanism that involves the Drp1-dependent regulation of kinesin-1 complex.
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PMID:Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle. 3204 98

Endocannabinoids (eCB) modulate growth cone dynamics and axonal pathfinding through the stimulation of cannabinoid type-1 receptors (CB1R), the function of which depends on their delivery and precise presentation at the growth cone surface. However, the mechanism involved in the axonal transport of CB1R and its transport role in eCB signaling remains elusive. As mutations in the kinesin-1 molecular motor have been identified in patients with abnormal cortical development and impaired white matter integrity, we studied the defects in axonal pathfinding and fasciculation in mice lacking the kinesin light chain 1 (Klc1 ^-/-) subunit of kinesin-1. Reduced levels of CB1R were found in corticofugal projections and axonal growth cones in Klc1 ^-/- mice. By live-cell imaging of CB1R-eGFP we characterized the axonal transport of CB1R vesicles and described the defects in transport that arise after KLC1 deletion. Cofilin activation, which is necessary for actin dynamics during growth cone remodeling, is impaired in the Klc1 ^-/- cerebral cortex. In addition, Klc1 ^-/- neurons showed expanded growth cones that were unresponsive to CB1R-induced axonal elongation. Together, our data reveal the relevance of kinesin-1 in CB1R axonal transport and in eCB signaling during brain wiring.
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PMID:Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance. 3226 98

Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long-distance transport of RNA granules is not yet understood. Here, we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts selectively with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that the binding of SFPQ to the KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie Tooth (CMT) disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations indicate that KIF5A-mediated SFPQ-RNA granule transport may be a key function disrupted in KIF5A-linked neurologic diseases and that replacing axonally translated proteins serves as a therapeutic approach to axonal degenerative disorders.
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PMID:Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival. 3328 22


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