Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kavar(21g), a dominant female-sterile mutation of Drosophila, identifies the alphaTubulin67C gene that encodes alpha4-tubulin, the maternally provided alpha-tubulin isoform. Although alpha4-tubulin is synthesized during oogenesis, its function is required only in the early cleavage embryos. However, once present in the developing oocyte, much of the alpha4-tubulin and the Kavar(21g)-encoded E426K-alpha4-tubulin molecules become incorporated into the microtubules. We analyzed ooplasmic streaming and lipid-droplet transport, with confocal reflection microscopy, in the developing egg primordia in the presence and absence of alpha4-tubulin and E426K-alpha4-tubulin and learnt that the E426K-alpha4-tubulin molecules eliminate ooplasmic streaming and alter lipid-droplet transport. Apparently, Glu426 is involved in stabilization of the microtubule-kinesin complexes when the kinesins are in the most labile, ADP-bound state. Replacement of Glu426 by Lys results in frequent detachments of the kinesins from the microtubules leading to reduced transport efficiency and death of the embryos derived from the Kavar(21g)-carrying females. Glu426 is a component of the twelfth alpha-helix, which is the landing and binding platform for the mechanoenzymes. Since the twelfth alpha-helix is highly conserved in the alpha-tubulin family, Glu415, which corresponds to Glu426 in the constitutively expressed alpha-tubulins, seems be a key component of microtubule-kinesin interaction and thus the microtubule-based transport.
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PMID:Glu415 in the alpha-tubulins plays a key role in stabilizing the microtubule-ADP-kinesin complexes. 1962 31

Microtubule (MT) binding accelerates the rate of ATP hydrolysis in kinesin. To understand the underlying mechanism, using charged-to-alanine mutational analysis, we identified two independent sites in tubulin, which are critical for kinesin motility, namely, a cluster of negatively charged residues spanning the helix 11-12 (H11-12) loop and H12 of alpha-tubulin, and the negatively charged residues in H12 of beta-tubulin. Mutation in the alpha-tubulin-binding site results in a deceleration of ATP hydrolysis (k(cat)), whereas mutation in the beta-tubulin-binding site lowers the affinity for MTs (K(0.5)MT). The residue E415 in alpha-tubulin seems to be important for coupling MT binding and ATPase activation, because the mutation at this site results in a drastic reduction in the overall rate of ATP hydrolysis, largely due to a deceleration in the reaction of ADP release. Our results suggest that kinesin binding at a region containing alpha-E415 could transmit a signal to the kinesin nucleotide pocket, triggering its conformational change and leading to the release of ADP.
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PMID:Key residues on microtubule responsible for activation of kinesin ATPase. 2022 48

Abeta is proteolytically produced from the Alzheimer's amyloid precursor protein (APP). Major properties attributed to Abeta include neurotoxic effects that contribute to Alzheimer's disease neurodegeneration. However, Abeta can also affect APP processing and trafficking that, in neurons, is anterogradelly transported via microtubules in a kinesin-associated manner. Herein we show that Abeta can induce accumulation of intracellular sAPP in primary neuronal cultures. Subcellular fractionation studies and immunofluorescence analysis revealed that upon Abeta exposure sAPP retention was localized to cytoskeleton associated vesicular structures along the neurite processes, positive for an APP N-terminal antibody and negative for an APP C-terminal antibody. These vesicular structures were also positive for kinesin light chain 1 (KLC). We confirm that Abeta alters both actin and microtubule networks. It increases F-actin polymerization and we report for the first time that Abeta decreases alpha-tubulin acetylation. The use of cytoskeleton associated drugs partially reversed the Abeta-induced effects on sAPP secretion. The data here presented show that Abeta causes intracellular sAPP retention by inducing alterations in the cytoskeleton network, thus contributing to impaired APP/sAPP vesicular transport. Moreover, the data strengthens the hypothesis that Abeta-induces neurodegeneration and provides a potential mechanism of action, as impaired vesicular and axonal transport have been linked to Alzheimer's disease pathology.
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PMID:Abeta promotes Alzheimer's disease-like cytoskeleton abnormalities with consequences to APP processing in neurons. 2034 56

Posttranslational microtubule modifications (PTMs) are numerous; however, the biochemical and cell biological roles of those modifications remain mostly an enigma. The Aspergillus nidulans kinesin-3 UncA uses preferably modified microtubules (MTs) as tracks for vesicle transportation. Here, we show that a positively charged region in the tail of UncA (amino acids 1316 to 1402) is necessary for the recognition of modified MTs. Chimeric proteins composed of the kinesin-1 motor domain and the UncA tail displayed the same specificity as UncA, suggesting that the UncA tail is sufficient to establish specificity. Interaction between the UncA tail and alpha-tubulin was shown using a yeast two-hybrid assay and in A. nidulans by bimolecular fluorescence complementation. This is the first demonstration of how a kinesin-3 motor protein distinguishes among different MT populations in fungal cells, and how specificity determination depends on the tail rather than the motor domain, as has been demonstrated for kinesin 1 in neuronal cells.
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PMID:The Aspergillus nidulans kinesin-3 tail is necessary and sufficient to recognize modified microtubules. 2236 25


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