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Single-molecule investigation of the interference between kinesin, tau and MAP2c
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Motor proteins and microtubule-associated proteins (MAPs) play important roles in cellular transport, regulation of shape and polarity of cells. While motor proteins generate motility, MAPs are thought to stabilize the microtubule tracks. However, the proteins also interfere with each other, such that MAPs are able to inhibit transport of vesicles and organelles in cells. In order to investigate the mechanism of MAP-motor interference in molecular detail, we have studied single kinesin molecules by total internal reflection fluorescence microscopy in the presence of different neuronal MAPs (tau, MAP2c). The parameters observed included run-length (a measure of processivity), velocity and frequency of attachment. The main effect of MAPs was to reduce the attachment frequency of motors. This effect was dependent on the concentration, the affinity to microtubules and the domain composition of MAPs. In contrast, once attached, the motors did not show a change in speed, nor in their run-length. The results suggest that MAPs can regulate motor activity on the level of initial attachment, but not during motion.
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“MAP2 has been shown to block the path of kinesin motors in in vitro assays (46, 47, 48, 49, 50).”
From Active transport by cytoplasmic dynein sustains dendritic MAP2 localization in developing neurons (2026) · cites this paper as [49]
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“…as box plots, which display the median value (line inside the box), upper quartile (top of the box), lower quartile (bottom of the box), 90th percentile (top whisker), 10th percentile (bottom whisker), and all values below the 10th and above the 90th percentile (potential outliers) shown as dots.”
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“Tau could also affect vesicle trafficking by inhibiting the binding of motor proteins such as kinesins to microtubules (Seitz et al., 2002).”
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“This is based on studies which documented organelle transport along MTs stabilized by paclitaxel [48].”
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“…with reports that ATPase activity and processivity of dynein were reduced by cleaving the E hook with subtilisin (Paschal et al, 1989; Wang and Sheetz, 2000), and that MAP binding to the right side of the protofilament decreases the run length for both kinesin and dynein (Seitz et al, 2002).”
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“The concept of MAPs influencing transport mechanisms is further supported by an in vitro study which demonstrated the direct impact of tau or MAP2c on dynamic parameters of kinesin binding to microtubules (Seitz et al. 2002).”
ResultModeling Tau Polymerization in Vitro: A Review and Synthesis
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“In addition, direct binding of tau to microtubules was found to reduce the attachment of kinesin motors (Seitz et al., 2002), which may account for the ability of tau to interfere with microtubule-associated transport of vesicles and organelles in cultured cells (Ebneth et al.”
BackgroundSelf-citationMicrotubule-targeted agents: When mitochondria become essential to chemotherapy
Rovini, A. M. F., Savry, A., Braguer, D., & Carré, M. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.01.001 · Cited by 108
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“In vitro studies using purified components of the AT system further supported a model where tau would elicit this effect by competing with conventional kinesin heavy chain subunits for microtubule binding (Seitz et al., 2002; Mandelkow et al., 2003).”
BackgroundTobacco Mosaic Virus Movement Protein Functions as a Structural Microtubule-Associated Protein
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“In agreement with previous reports (93), the average kinesin-dependent microtubule transVOL.”
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“In vivo, cargo delivery is slowed further by MAPs that obstruct and reduce motor protein processivity (39).”
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Self-citationDrosophila Ensconsin Promotes Productive Recruitment of Kinesin-1 to Microtubules
Sung, H.-H., Telley, I. A., Papadaki, P., Ephrussi, A., Surrey, T., & Rørth, P. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.10.006 · Cited by 100
Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy
Caillet‐Boudin, M., Fernández-Gómez, F.-J., Tran, H., Dhaenens, C., Buée, L., & Sergeant, N. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2013.00057 · Cited by 107
“…Tau affects organelle transport by reducing the attachment frequency of motors to microtubules (Sato-Harada et al., 1996; Trinczek et al., 1999; Seitz et al., 2002; Mandelkow et al., 2004) or differentially regulating kinesin- and dynein-based transport (Dixit et al., 2008; Vershinin et al.,…”
BackgroundKwinter, D. M., Lo, K. Y., Mafi, P., & Silverman, M. A. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.05.038 · Cited by 98
Modulation of kinesin binding by the C‐termini of tubulin
Skiniotis, G., Cochran, J. C., Müller, J., Mandelkow�, E., Gilbert, S. P., & Hoenger, A. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600118 · Cited by 94
“One could speculate that MAPs, by saturating the charged CTTs, may impose a similar rigor state on kinesin as caused by their removal, thereby stalling the processive walk (Ebneth et al, 1998; Seitz et al, 2002), but still allow kinesin motors to decorate MTs fully (unpublished results).”
Self-citationDunne, P. W., Lester, E. H., & Walton, R. I. (2016) · Reaction Chemistry & Engineering · doi:10.1039/c6re00107f · Cited by 103
Site-Specific Nitration Differentially Influences τ Assembly in Vitro
Reynolds, M. R., Berry, R. W., & Binder, L. I. (2005) · Biochemistry · doi:10.1021/bi051028w · Cited by 96
Microtubule lattice spacing governs cohesive envelope formation of tau family proteins
Siahaan, V., Tan, R., Humhalova, T., Libusova, L., Lacey, S. E., Tan, T., Dacy, M., Ori-McKenney, K. M., McKenney, R. J., Braun, M., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01096-2 · Cited by 94
Gilley, J., Seereeram, A., Ando, K., Mosely, S. I. S., Andrews, S., Kerschensteiner, M., Misgeld, T., Brion, J., Anderton, B. H., Hanger, D. P., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.02.014 · Cited by 94
“The fact that mitochondrial speeds are largely unaltered is also consistent with the model, with the frequency of kinesin attachment to MTs, rather than subsequent movement, being critical (Dixit et al., 2008; Seitz et al., 2002; Trinczek et al., 1999).”
Tau and Axonal Transport Misregulation in Tauopathies
Combs, B., Mueller, R. L., Morfini, G. A., Brady, S. T., & Kanaan, N. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_7 · Cited by 96
McVicker, D. P., Chrin, L. R., & Berger, C. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.292987 · Cited by 85
Axonal Transport Defects in Alzheimer’s Disease
Wang, Z., Tan, L., & Yu, J. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8810-x · Cited by 92
“(2) Excessive monomeric tau can lead to defects in AT by competing with motor proteins to bind with microtubules, which prevents the motor proteins from moving along the microtubules [55].”
Microtubule-associated Protein-like Binding of the Kinesin-1 Tail to Microtubules
Seeger, M. A., & Rice, S. E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.068247 · Cited by 86
Visual Arrestin Binding to Microtubules Involves a Distinct Conformational Change
Hanson, S. M., Francis, D. J., Vishnivetskiy, S. A., Klug, C. S., & Gurevich, V. V. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510738200 · Cited by 84
Inhibition of APP Trafficking by Tau Protein Does Not Increase the Generation of Amyloid‐β Peptides
Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P., Biernat, J., Mandelkow, E., & Mandelkow, E. (2006) · Traffic · doi:10.1111/j.1600-0854.2006.00434.x · Cited by 82
“Adding these two sets of observations, one would expect that any mechanism that would retard the trafficking of APP vesicles and increase the dwell time of APP vesicles during transit, such as increasing the amount of tau on MTs, would therefore increase the probability of Ab generation.”
BackgroundInfluentialSelf-citationTesco, G., & Lomoio, S. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101628 · Cited by 102
Tau binding to microtubules does not directly affect microtubule‐based vesicle motility
Morfini, G. A., Pigino, G. F., Mizuno, N., Kikkawa, M., & Brady, S. T. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21154 · Cited by 84
“The effect of different tau constructs in these assays did not correlate with their affinity of binding to MTs, MT assembly properties, or net charge (Seitz et al., 2002).”
BackgroundResultInfluentialRegulation of Cytoplasmic Dynein ATPase by Lis1
Mesngon, M. T., Tarricone, C., Sachin Hebbar, C., Guillotte, A. M., Schmitt, E. W., Lanier, L. M., Musacchio, A., King, S. J., & Smith, D. S. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5095-05.2006 · Cited by 79
“Another microtubule binding protein, tau, has been shown to influence axon transport (Seitz et al., 2002).”
BackgroundRole of Microtubules in Fusion of Post-Golgi Vesicles to the Plasma Membrane
Schmoranzer, J., & Simon, S. M. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-08-0500 · Cited by 79
“Recently, it was reported that tau expression in mammalian cells affects the attachment of plus-end–directed vesicles to the microtubules, whereas the velocity of movement and the run-length are not altered by expression of tau (Seitz et al., 2002).”
BackgroundPaclitaxel increases axonal localization and vesicular trafficking of Nav1.7
Akin, E. J., Alsaloum, M., Higerd‐Rusli, G. P., Liu, S., Zhao, P., Dib-Hajj, F. B., Waxman, S. G., & Dib‐Hajj, S. D. (2021) · Brain · doi:10.1093/brain/awab113 · Cited by 74
“finity of kinesin motors for microtubules, or their ability to navigate the microtubules.(35,36) Thus, it is possible that low”
BackgroundMolecular mechanisms for organizing the neuronal cytoskeleton
Mukhopadhyay, R., Kumar, S., & Hoh, J. H. (2004) · BioEssays · doi:10.1002/bies.20088 · Cited by 74
Tau‐Induced Traffic Jams Reflect Organelles Accumulation at Points of Microtubule Polar Mismatching
Shemesh, O. A., Erez, H., Ginzburg, I., & Spira, M. E. (2007) · Traffic · doi:10.1111/j.1600-0854.2007.00695.x · Cited by 72
“In an attempt to link tau overexpression, inhibition of axonal transport and neurodegeneration, a molecular cascade was suggested wherein excess tau initially binds to microtubules (MTs) and competes with MT–kinesin-binding sites, thereby downregulating anterograde axoplasmic transport (9).”
BackgroundMechanism and regulation of kinesin‐5, an essential motor for the mitotic spindle
Waitzman, J. S., & Rice, S. E. (2013) · Biology of the Cell · doi:10.1111/boc.201300054 · Cited by 73
“Previous studies proposed mechanisms by which MAPs could regulate kinesin motors through local MT lattice alteration and/or competition for MT binding sites (Seitz et al., 2002; McVicker et al., 2011).”
BackgroundKorten, T., & Diez, S. (2008) · Lab on a Chip · doi:10.1039/b803585g · Cited by 76
Ramser, E. M., Gan, K. J., Decker, H., Fan, E. Y., Suzuki, M. M., Ferreira, S. T., & Silverman, M. A. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-12-0858 · Cited by 74
“AβOs disrupt BDNF transport independent of tau Recent studies suggest that tau impairs transport by promoting motor protein dissociation from microtubules (Seitz et al., 2002) or disrupting motor protein–cargo interactions (Kanaan et al., 2011).”
Intracellular cargo transport by kinesin-3 motors
Siddiqui, N., & Straube, A. (2017) · Biochemistry (Moscow) · doi:10.1134/s0006297917070057 · Cited by 71
Kinesin-1 Motors Can Circumvent Permanent Roadblocks by Side-Shifting to Neighboring Protofilaments
Schneider, R., Korten, T., Walter, W. J., & Diez, S. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.03.048 · Cited by 71
Liazoghli, D., Perreault, S., Micheva, K. D., Desjardins, M., & Leclerc, N. M. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62366-8 · Cited by 70
“Tau would affect vesicle trafficking by inhibiting the binding of motor proteins such as kinesins to microtubules as suggested by an in vitro competition assay.(15) In a neuron, the transport of membranous vesicles in dendrites and the axon is essential for the maintenance of synapse integrity.”
BackgroundZheng, Y., Zhang, X., & Chen, Z. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13122 · Cited by 72
Ross, J. L. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.07.037 · Cited by 66
Aβ, tau and ApoE4 in Alzheimer's disease: the axonal connection
Adalbert, R., Gilley, J., & Coleman, M. P. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.02.004 · Cited by 65
Shemesh, O. A., & Spira, M. E. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.03.008 · Cited by 63
“Initially, excess tau binds to microtubules (MTs) and competes with MT-kinesin binding sites, thereby downregulating anterograde axoplasmic transport (Seitz et al., 2002).”
Background
Metadata
- Authors
- Seitz, A., Kojima, H., Oiwa, K., Mandelkow, E.-M., Song, Y.-H., & Mandelkow, E.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Corresponding author
- Seitz, Arne
- Venue
- The EMBO Journal
- Published
- 2002-09-16
- Volume
- 21
- Issue
- 18
- Pages
- 4896-4905
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126299
- OpenAlex
- W1968991344
- Cited by
- 257
- References
- 49
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 7 · 2017: 15 · 2016: 11 · 2015: 12 · 2014: 18 · 2013: 10 · 2012: 12
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- kinesin, tau protein, MAP2c, microtubule-associated proteins, microtubule stabilization, single-molecule tracking, total internal reflection fluorescence microscopy, run length, processivity, motor speed, neuronal transport
- MeSH terms
- Adenosine Triphosphatases, Animals, Biological Transport, Humans, Isoelectric Point, Microscopy, Fluorescence, Microtubule-Associated Proteins, Microtubules, Models, Biological, Protein Binding, Recombinant Proteins, Kinesins, tau Proteins, Genes, Reporter, Protein Isoforms, Molecular Motor Proteins, Rats
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