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)

Microtubules and their associated proteins form the basis of axonal transport; they are degraded during the neuronal degeneration in Alzheimer's disease. This article surveys recent results on the structure of microtubules, tau protein, and PHFs. Microtubules have been investigated by electron microscopy and image processing after labeling them with the head domain of the motor protein kinesin. This reveals the arrangement of tubulin subunits in microtubules and the shape of the tubulin-motor complex. Tau protein was studied by electron microscopy, solution X-ray scattering, and spectroscopic methods. It appears as an elongated molecule (about 35 nm) without recognizable secondary structure. Alzheimer PHFs were examined by FTIR and X-ray diffraction; they, too, show evidence for secondary structure such as beta sheets.
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PMID:On the structure of microtubules, tau, and paired helical filaments. 756 44

Using several in vitro motility assays, we found that motility driven by the microtubule (MT) motors, kinesin and cytoplasmic dynein, could be inhibited by MAP2 but not by tau protein or the MT-binding proteolytic fragment of MAP2. In MT gliding assays, even the presence of one MAP2 molecule per sixty-nine tubulin dimers caused an inhibition of about 75% of MT motility at low concentrations of both motors. The percent inhibition of motility decreased with increasing concentration of either motor, suggesting that the inhibition was the result of competition for access to the MT surface. The decrease in the number of moving MTs with MAP2 was correlated with an increase in the frequency of release of moving MTs from the motor-coated glass. In assays of in vitro vesicular organelle motility and formation of ER networks, the presence of MAP2 inhibited small vesicle movements and to a lesser extent ER network formation. To determine if competition for specific sites on the MT or coating of the MT surface inhibited motility, we used tau protein and the chymotryptic MT-binding fragments of MAP2 to coat MTs. No inhibition was observed and there was even an increase in the number of attached and moving MTs in the gliding assay with tau-coated MTs. Because MAP2, tau and the chymotryptic MT-binding fragments of MAP2 bind to the same domain on tubulin, masking of the MT surface sites does not appear responsible for the inhibition of motility by MAP2. Rather, we suggest that the sidearm of MAP2 interfered with the interaction of motors with MTs and caused a dramatic increase in the rate of MT release. In vivo, MAP2 could play a major role in the generation of cellular polarity even at substoichiometric levels by inhibiting transport on microtubules in specific domains of the cytoplasm.
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PMID:Steric inhibition of cytoplasmic dynein and kinesin motility by MAP2. 831 63

The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins. Mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. These effects are caused by tau's binding to microtubules and slowing down intracellular transport by preferential impairment of plus-end-directed transport mediated by kinesin-like motor proteins. Since in Alzheimer's disease tau protein is elevated and mislocalized, these observations point to a possible cause for the gradual degeneration of neurons.
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PMID:Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. 981 97

We have performed a real time analysis of fluorescence-tagged vesicle and mitochondria movement in living CHO cells transfected with microtubule-associated protein tau or its microtubule-binding domain. tau does not alter the speed of moving vesicles, but it affects the frequencies of attachment and detachment to the microtubule tracks. Thus, tau decreases the run lengths both for plus-end and minus-end directed motion to an equal extent. Reversals from minus-end to plus-end directed movement of single vesicles are strongly reduced by tau, but reversals in the opposite direction (plus to minus) are not. Analogous effects are observed with the transport of mitochondria and even with that of vimentin intermediate filaments. The net effect is a directional bias in the minus-end direction of microtubules which leads to the retraction of mitochondria or vimentin IFs towards the cell center. The data suggest that tau can control intracellular trafficking by affecting the attachment and detachment cycle of the motors, in particular by reducing the attachment of kinesin to microtubules, whereas the movement itself is unaffected.
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PMID:Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. 1038 91

We studied the effect of microtubule-associated tau protein on trafficking of vesicles and organelles in primary cortical neurons, retinal ganglion cells, and neuroblastoma cells. Tau inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites. Loss of peroxisomes makes cells vulnerable to oxidative stress and leads to degeneration. In particular, tau inhibits transport of amyloid precursor protein (APP) into axons and dendrites, causing its accumulation in the cell body. APP tagged with yellow fluorescent protein and transfected by adenovirus associates with vesicles moving rapidly forward in the axon (approximately 80%) and slowly back (approximately 20%). Both movements are strongly inhibited by cotransfection with fluorescently tagged tau (cyan fluorescent protein-tau) as seen by two-color confocal microscopy. The data suggests a linkage between tau and APP trafficking, which may be significant in Alzheimer's disease.
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PMID:Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. 1190 Nov 70

Pathological alterations in the microtubule-associated protein (MAP) tau are well-established in a number of neurodegenerative disorders, including Alzheimer's Disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. Tau protein and in some cases, neurofilament subunits exhibit abnormal phosphorylation on specific serine and threonine residues in these diseases. A large body of biochemical, genetic, and cell biological evidence implicate two major serine-threonine protein kinases, glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase 5 (CDK5) as major kinases responsible for both normal and pathological phosphorylation of tau protein in vivo. What remains unclear is whether tau phosphorylation and/or neurofibrillary tangle (NFT) formation are causal or secondary to initiation of neuronal pathology. In fact, many studies have indicated that tau misphosphorylation is not the causal event. Interestingly, some of these kinase and phosphatase activities have recently merged as key regulators of fast axonal transport (FAT). Specifically, CDK5 and GSK-3 have been recently shown to regulate kinesin-driven motility. Given the essential role of FAT in neuronal function, an alternate model for pathogenesis can be proposed. In this model, misregulation of FAT induced by an imbalance in specific kinase-phosphatase activities within neurons represents an early and critical step for the initiation of neuronal pathology. Such a model may explain many of the unique characteristics of late onset of neurological diseases such as AD.
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PMID:Fast axonal transport misregulation and Alzheimer's disease. 1242 5

ncd is a minus-end directed, kinesin-like motor, which binds to microtubules with its motor domain and its cargo domain as well. Typical of retrograde motors, the motor domain of ncd locates to the C-terminal end of the polypeptide chain, and hence, the cargo domain constitutes the N-terminal region. To date, several studies have investigated the interaction properties of the motor domain with microtubules, but very few structural data are available about the tail itself or its interaction with microtubules as cargo. Here, we applied cryo-electron microscopy and helical 3D image reconstruction to 15 protofilament microtubules decorated with an ncd tail fragment (N-terminal residues 83-187, named NT6). In our study, the ncd tail shows a behaviour resembling filamentous MAPs such as tau protein, exhibiting a highly flexible structure with no large globular domains. NT6 binds to four different sites on the outer side of microtubules within the proximity of the kinesin motor-binding site. Two of these sites locate within the groove between two neighbouring protofilaments, and appear as strong binding sites, while the other two sites, located at the outer rim, appear to play a secondary role. In addition, the ncd tail fragment induces the formation of large protofilament sheets, suggesting a tail-induced modification of lateral protofilament contacts.
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PMID:A structural analysis of the interaction between ncd tail and tubulin protofilaments. 1455 43

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with beta-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-alpha Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, beta-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.
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PMID:Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease. 1619 23

Tau protein is a major microtubule (MT)-associated brain protein enriched in axons. Multiple functional roles are proposed for tau protein, including MT stabilization, generation of cell processes, and targeting of phosphotransferases to MTs. Recently, experiments involving exogenous tau expression in cultured cells suggested a role for tau as a regulator of kinesin-1-based motility. Tau was proposed to inhibit attachment of kinesin-1 to MTs by competing for the kinesin-1 binding site. In this work, we evaluated effects of tau on fast axonal transport (FAT) by using vesicle motility assays in isolated squid axoplasm. Effects of recombinant tau constructs on both kinesin-1 and cytoplasmic dynein-dependent FAT rates were evaluated by video microscopy. Exogenous tau binding to endogenous squid MTs was evidenced by a dramatic change in individual MT morphologies. However, perfusion of tau at concentrations approximately 20-fold higher than physiological levels showed no effect on FAT. In contrast, perfusion of a cytoplasmic dynein-derived peptide that competes with kinesin-1 and cytoplasmic dynein binding to MTs in vitro rapidly inhibited FAT in both directions. Taken together, our results indicate that binding of tau to MTs does not directly affect kinesin-1- or cytoplasmic dynein-based motilities. In contrast, our results provide further evidence indicating that the functional binding sites for kinesin-1 and cytoplasmic dynein on MTs overlap.
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PMID:Tau binding to microtubules does not directly affect microtubule-based vesicle motility. 1726 63

The products of the Herpes simplex (HSV-1) genome interact with many Alzheimer's disease susceptibility genes or proteins. These in turn affect those of the virus. For example, HSV-1 binds to heparan sulphate proteoglycans (HSPG2), or alpha-2-macroglobulin (A2M), and enters cells via nectin receptors, which are cleaved by gamma-secretase (APH1B, PSEN1, PSEN2, PEN2, NCSTN). The virus also binds to blood-borne lipoproteins and apolipoprotein E (APOE) is able to modify its infectivity. Viral uptake is cholesterol- and lipid raft-dependent (DHCR24, HMGCR, FDPS, RAFTLIN, SREBF1). The virus is transported to the nucleus via the dynein and kinesin (KNS2) motors associated with the microtubule network (MAPT). Amyloid precursor protein (APP) plays a role in this transport. Nuclear export is mediated via disruption of the nuclear lamina and binding to LMNA. Herpes simplex activates kinases (CDC2 and casein kinase 2) whose substrates include APOE, APP, MAPT, PSEN2, and SREBF1. A viral protein is also able to delete mitochondrial DNA, a situation prevalent in Alzheimer's disease. The virus binds to the host transcription factors transcription factor CP2 (TFCP2) and POU2F1 that control many other genes associated with Alzheimer's disease. Viral latency is controlled by IL6 and IL1B and at different stages of its life cycle the virus can either promote or attenuate apoptosis via Fas and tumor necrosis factor pathways (FAS, TNF, DAPK1, PARP1). Viral evasion strategies include inhibition of the antigen processor TAP2, the production of an Fc immunoglobulin receptor mimic (FCER1G) and inhibition of the viral-activated kinase EIF2AK2. These and other host/viral interactions, targeted to certain Alzheimer's disease susceptibility genes, support the idea that some form of synergy between the pathogen and genetic factors may play a role in the pathology of late-onset Alzheimer's disease.
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PMID:Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades. 1816 3


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