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)

In order to investigate the microtubule-associated intracellular trafficking of the NH2-terminal cellular prion protein (PrPC) fragment [Biochem. Biophys. Res. Commun. 313 (2004) 818], we performed a real-time imaging of fluorescent PrPC (GFP-PrPC) in living cells. Such GFP-PrPC exhibited an anterograde movement towards the direction of plasma membranes at a speed of 140-180 nm/s, and a retrograde movement inwardly at a speed of 1.0-1.2 microm/s. The anterograde and retrograde movements of GFP-PrPC were blocked by a kinesin family inhibitor (AMP-PNP) and a dynein family inhibitor (vanadate), respectively. Furthermore, anti-kinesin antibody (alpha-kinesin) blocked its anterograde motility, whereas anti-dynein antibody (alpha-dynein) blocked its retrograde motility. These data suggested the kinesin family-driven anterograde and the dynein-driven retrograde movements of GFP-PrPC. Mapping of the interacting domains of PrPC identified amino acid residues indispensable for interactions with kinesin family: NH2-terminal mouse (Mo) residues 53-91 and dynein: NH2-terminal Mo residues 23-33, respectively. Our findings argue that the discrete N-terminal amino acid residues are indispensable for the anterograde and retrograde intracellular movements of PrPC.
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PMID:Anterograde and retrograde intracellular trafficking of fluorescent cellular prion protein. 1498 83

Our previous studies have demonstrated that prion protein (PrP) leads to disassembly of microtubular cytoskeleton through binding to tubulin and its oligomerization. Here we found that PrP-treated cells exhibited improper morphology of mitotic spindles. Formation of aberrant spindles may result not only from altered microtubule dynamics - as expected from PrP-induced tubulin oligomerization - but also from impairing the function of molecular motors. Therefore we checked whether binding of PrP to microtubules affected movement generated by Ncd - a kinesin responsible for the proper organization of division spindles. We found that PrP inhibited Ncd-driven transport of microtubules. Most probably, the inhibition of the microtubule movement resulted from PrP-induced changes in the microtubule structure since Ncd-microtubule binding was reduced already at low PrP to tubulin molar ratios. This study suggests another plausible mechanism of PrP cytotoxicity related to the interaction with tubulin, namely impeding microtubule-dependent transport.
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PMID:Prion protein impairs kinesin-driven transport. 2288 85

Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases.
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PMID:Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2. 2926 64

There is increasing evidence that tau protein behaves in a prion-like manner in tauopathy. The stabilization of tau protein using a small molecular compound can limit tauopathy associated morbidity that advances with ageing. Here, a lab-on-a-chip experiment is reported, where gold citrate nanoparticles (5 nm, AuNPs) can remodel mutant tau protein (P301L) and prion, thus resolving the mutant tau- and prion-mediated impairment of kinesin cargo transport on microtubules. It is found that tau protein is overexpressed in Alzheimer's disease (AD) patient serum samples and the tau conformational change can also be affected in human serum samples of AD when treated with AuNPs ex vivo. Similarly, AuNPs reorganizing the prion protein and inducing conformational changes of prions in AD serum have been observed, while having no effect on alpha-synuclein in Parkinson patient serum. The mapping of AD serum mediated traffic jams, using particle tracking and mean square displacement analysis, and the observed recovery of uninterrupted processive motor functions by AuNP treatment show that kinesin cargo assays might be a useful method for future ex vivo validation of a targeted therapy against tauopathy before administration, a viable option to combat various neurodegenerative disorders arising from the susceptibility of amyloidogenic proteins toward aggregation.
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PMID:Remodeling Tau and Prion Proteins Using Nanochaperons. 3264 92