skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Abstract

Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer’s. We report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; ΦTau = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to PB ~ 10,000–20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (PB ~ 1,000–2,000 Pa) over the same range. Remarkably, the abrupt increase in PB observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < ΦTau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT–MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling becausemore » the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Univ. of California, Santa Barbara, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Materials Sciences & Engineering Division; National Science Foundation (NSF); National Institutes of Health (NIH); National Research Foundation of Korea (NRF); Israel Science Foundation (ISF); United States-Israel Binational Science Foundation (BSF)
OSTI Identifier:
1235187
Alternate Identifier(s):
OSTI ID: 1469100
Grant/Contract Number:  
FG02-06ER46314; DMR-1401784; R01-NS13560; R01-NS35010; 2011-0031931; 2014-R1A1A2A16055715; 1565/13; 2009271
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 112 Journal Issue: 47; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Tau; intrinsically disordered proteins; microtubule; SAXS; force measurement

Citation Formats

Chung, Peter J., Choi, Myung Chul, Miller, Herbert P., Feinstein, H. Eric, Raviv, Uri, Li, Youli, Wilson, Leslie, Feinstein, Stuart C., and Safinya, Cyrus R. Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules. United States: N. p., 2015. Web. doi:10.1073/pnas.1513172112.
Chung, Peter J., Choi, Myung Chul, Miller, Herbert P., Feinstein, H. Eric, Raviv, Uri, Li, Youli, Wilson, Leslie, Feinstein, Stuart C., & Safinya, Cyrus R. Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules. United States. doi:https://doi.org/10.1073/pnas.1513172112
Chung, Peter J., Choi, Myung Chul, Miller, Herbert P., Feinstein, H. Eric, Raviv, Uri, Li, Youli, Wilson, Leslie, Feinstein, Stuart C., and Safinya, Cyrus R. Thu . "Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules". United States. doi:https://doi.org/10.1073/pnas.1513172112.
@article{osti_1235187,
title = {Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules},
author = {Chung, Peter J. and Choi, Myung Chul and Miller, Herbert P. and Feinstein, H. Eric and Raviv, Uri and Li, Youli and Wilson, Leslie and Feinstein, Stuart C. and Safinya, Cyrus R.},
abstractNote = {Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer’s. We report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; ΦTau = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to PB ~ 10,000–20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (PB ~ 1,000–2,000 Pa) over the same range. Remarkably, the abrupt increase in PB observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < ΦTau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT–MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.},
doi = {10.1073/pnas.1513172112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 47,
volume = 112,
place = {United States},
year = {2015},
month = {11}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: https://doi.org/10.1073/pnas.1513172112

Citation Metrics:
Cited by: 20 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Gel-expanded to gel-condensed transition in neurofilament networks revealed by direct force measurements
journal, November 2009

  • Beck, Roy; Deek, Joanna; Jones, Jayna B.
  • Nature Materials, Vol. 9, Issue 1
  • DOI: 10.1038/nmat2566

A protein factor essential for microtubule assembly.
journal, May 1975

  • Weingarten, M. D.; Lockwood, A. H.; Hwo, S. Y.
  • Proceedings of the National Academy of Sciences, Vol. 72, Issue 5
  • DOI: 10.1073/pnas.72.5.1858

Microtubule Protofilament Number Is Modulated in a Stepwise Fashion by the Charge Density of an Enveloping Layer
journal, January 2007


Tau protein binding forms a 1nm thick layer along protofilaments without affecting the radial elasticity of microtubules
journal, June 2007

  • Schaap, Iwan A. T.; Hoffmann, Bernd; Carrasco, Carolina
  • Journal of Structural Biology, Vol. 158, Issue 3
  • DOI: 10.1016/j.jsb.2006.11.010

Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau.
journal, October 1992

  • Drechsel, D. N.; Hyman, A. A.; Cobb, M. H.
  • Molecular Biology of the Cell, Vol. 3, Issue 10
  • DOI: 10.1091/mbc.3.10.1141

Interplay between Liquid Crystalline and Isotropic Gels in Self-Assembled Neurofilament Networks
journal, July 2008


Transformation of taxol-stabilized microtubules into inverted tubulin tubules triggered by a tubulin conformation switch
journal, January 2014

  • Ojeda-Lopez, Miguel A.; Needleman, Daniel J.; Song, Chaeyeon
  • Nature Materials, Vol. 13, Issue 2
  • DOI: 10.1038/nmat3858

The distribution of tau in the mammalian central nervous system
journal, October 1985


Composite bottlebrush mechanics: α-internexin fine-tunes neurofilament network properties
journal, January 2015

  • Kornreich, M.; Malka-Gibor, E.; Laser-Azogui, A.
  • Soft Matter, Vol. 11, Issue 29
  • DOI: 10.1039/C5SM00662G

Assembly of Biological Nanostructures: Isotropic and Liquid Crystalline Phases of Neurofilament Hydrogels
journal, March 2015


Synchrotron X-ray Diffraction Study of Microtubules Buckling and Bundling under Osmotic Stress: A Probe of Interprotofilament Interactions
journal, November 2004


Assembly and structure of neurofilaments
journal, March 2003

  • Janmey, Paul A.; Leterrier, Jean-Francois; Herrmann, Harald
  • Current Opinion in Colloid & Interface Science, Vol. 8, Issue 1
  • DOI: 10.1016/S1359-0294(03)00010-4

Electrophoresis of individual microtubules in microchannels
journal, April 2007

  • van den Heuvel, M. G. L.; de Graaff, M. P.; Lemay, S. G.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 19
  • DOI: 10.1073/pnas.0608316104

Monte Carlo Simulations of Tau Proteins: Effect of Phosphorylation
journal, October 2010


Substoichiometric Binding of Taxol Suppresses Microtubule Dynamics
journal, February 1995

  • Derry, W. Brent; Wilson, Leslie; Jordan, Mary Ann
  • Biochemistry, Vol. 34, Issue 7
  • DOI: 10.1021/bi00007a014

Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease.
journal, June 1986

  • Kosik, K. S.; Joachim, C. L.; Selkoe, D. J.
  • Proceedings of the National Academy of Sciences, Vol. 83, Issue 11
  • DOI: 10.1073/pnas.83.11.4044

Electrostatic interaction between two cylindrical soft particles
journal, May 2009


The three-dimensional structure of tubulin protofilaments
journal, June 1979


Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons
journal, December 1992

  • Chen, J.; Kanai, Y.; Cowan, N. J.
  • Nature, Vol. 360, Issue 6405
  • DOI: 10.1038/360674a0

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration
journal, June 2004

  • Bunker, Janis M.; Wilson, Leslie; Jordan, Mary Ann
  • Molecular Biology of the Cell, Vol. 15, Issue 6
  • DOI: 10.1091/mbc.E04-01-0062

Low resolution structure of microtubules in solution
journal, July 1992


Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy After Repetitive Head Injury
journal, July 2009

  • McKee, Ann C.; Cantu, Robert C.; Nowinski, Christopher J.
  • Journal of Neuropathology & Experimental Neurology, Vol. 68, Issue 7
  • DOI: 10.1097/NEN.0b013e3181a9d503

The microtubule binding domain of tau protein
journal, June 1989


The Many Faces of Tau
journal, May 2011


Tau stabilizes microtubules by binding at the interface between tubulin heterodimers
journal, June 2015

  • Kadavath, Harindranath; Hofele, Romina V.; Biernat, Jacek
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 24
  • DOI: 10.1073/pnas.1504081112

Microtubule Polymerization Dynamics
journal, November 1997


The Conformational Ensembles of α-Synuclein and Tau: Combining Single-Molecule FRET and Simulations
journal, November 2012


Modeling of the 3RS tau protein with self-consistent field method and Monte Carlo simulation
journal, January 2010

  • Leermakers, F. A. M.; Jho, Y. -S.; Zhulina, E. B.
  • Soft Matter, Vol. 6, Issue 21
  • DOI: 10.1039/c0sm00191k

Developmentally regulated expression of specific tau sequences
journal, April 1989


Equilibrium distribution of flexible polymer chains between a macroscopic solution phase and small voids
journal, September 1967


Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains.
journal, April 1989

  • Himmler, A.; Drechsel, D.; Kirschner, M. W.
  • Molecular and Cellular Biology, Vol. 9, Issue 4
  • DOI: 10.1128/MCB.9.4.1381

Structure and Viscosity of Interpenetrating Polyelectrolyte Chains
journal, February 1987


Alzheimer Mechanisms and Therapeutic Strategies
journal, March 2012


Structural memory of natively unfolded tau protein detected by small-angle X-ray scattering
journal, May 2011

  • Shkumatov, Alexander V.; Chinnathambi, Subashchandrabose; Mandelkow, Eckhard
  • Proteins: Structure, Function, and Bioinformatics, Vol. 79, Issue 7
  • DOI: 10.1002/prot.23033

Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease
journal, July 2003

  • Panda, D.; Samuel, J. C.; Massie, M.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 16
  • DOI: 10.1073/pnas.1633508100

Random-coil behavior and the dimensions of chemically unfolded proteins
journal, August 2004

  • Kohn, J. E.; Millett, I. S.; Jacob, J.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 34
  • DOI: 10.1073/pnas.0403643101

Tau Is Enriched on Dynamic Microtubules in the Distal Region of Growing Axons
journal, June 1996


Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
journal, June 1998

  • Hutton, Mike; Lendon, Corinne L.; Rizzu, Patrizia
  • Nature, Vol. 393, Issue 6686
  • DOI: 10.1038/31508

Tau protein binds to microtubules through a flexible array of distributed weak sites
journal, November 1991


Molecular dynamics simulations of tubulin structure and calculations of electrostatic properties of microtubules
journal, May 2005

  • Tuszyński, J. A.; Brown, J. A.; Crawford, E.
  • Mathematical and Computer Modelling, Vol. 41, Issue 10
  • DOI: 10.1016/j.mcm.2005.05.002

From The Cover: Higher-order assembly of microtubules by counterions: From hexagonal bundles to living necklaces
journal, November 2004

  • Needleman, D. J.; Ojeda-Lopez, M. A.; Raviv, U.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 46
  • DOI: 10.1073/pnas.0406076101

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17
journal, October 1998

  • Clark, L. N.; Poorkaj, P.; Wszolek, Z.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 22
  • DOI: 10.1073/pnas.95.22.13103

The primary structure and heterogeneity of tau protein from mouse brain
journal, January 1988


Concentration and Solvency Effects on the Pair Interaction between Colloidal Particles in a Solution of Nonadsorbing Polymer
journal, November 2004

  • Tuinier, Remco; Fleer, Gerard J.
  • Macromolecules, Vol. 37, Issue 23
  • DOI: 10.1021/ma048571p

Domain Conformation of Tau Protein Studied by Solution Small-Angle X-ray Scattering
journal, September 2008

  • Mylonas, Efstratios; Hascher, Antje; Bernadó, Pau
  • Biochemistry, Vol. 47, Issue 39
  • DOI: 10.1021/bi800900d

Refined structure of αβ-tubulin at 3.5 Å resolution 1 1Edited by I. A. Wilson
journal, November 2001

  • Löwe, J.; Li, H.; Downing, K. H.
  • Journal of Molecular Biology, Vol. 313, Issue 5
  • DOI: 10.1006/jmbi.2001.5077

Interactions between sickle hemoglobin fibers
journal, September 2002

  • Jones, Christopher W.; Wang, Jiang Cheng; Ferrone, Frank A.
  • Faraday Discussions, Vol. 123
  • DOI: 10.1039/b207388a

Regulation and aggregation of intrinsically disordered peptides
journal, February 2015

  • Levine, Zachary A.; Larini, Luca; LaPointe, Nichole E.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 9
  • DOI: 10.1073/pnas.1418155112

Radial Compression of Microtubules and the Mechanism of Action of Taxol and Associated Proteins
journal, November 2005


Kinetic stabilization of microtubule dynamic instability in vitro by vinblastine
journal, February 1993

  • Toso, Robert J.; Jordan, Mary Ann; Farrell, Kevin W.
  • Biochemistry, Vol. 32, Issue 5
  • DOI: 10.1021/bi00056a013

The interaction between two cylinder shaped colloidal particles
journal, January 1959


Tubulin requires tau for growth onto microtubule initiating sites.
journal, November 1976

  • Witman, G. B.; Cleveland, D. W.; Weingarten, M. D.
  • Proceedings of the National Academy of Sciences, Vol. 73, Issue 11
  • DOI: 10.1073/pnas.73.11.4070

Structure of tubulin at 6.5 Å and location of the taxol-binding site
journal, June 1995

  • Nogales, Eva; Grayer Wolf, Sharon; Khan, Israr A.
  • Nature, Vol. 375, Issue 6530
  • DOI: 10.1038/375424a0

Statistics of macromolecular solutions trapped in small pores
journal, January 1977


Domains of tau Protein and Interactions with Microtubules
journal, October 1994

  • Gustke, N.; Trinczek, B.; Biernat, J.
  • Biochemistry, Vol. 33, Issue 32
  • DOI: 10.1021/bi00198a017

Colloid stabilization with grafted polyelectrolytes
journal, May 1991


Mutation in the tau gene in familial multiple system tauopathy with presenile dementia
journal, June 1998

  • Spillantini, M. G.; Murrell, J. R.; Goedert, M.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 13
  • DOI: 10.1073/pnas.95.13.7737

Microtubule bundling by tau proteins in vivo: analysis of functional domains.
journal, November 1992


Cationic liposome-microtubule complexes: Pathways to the formation of two-state lipid-protein nanotubes with open or closed ends
journal, July 2005

  • Raviv, U.; Needleman, D. J.; Li, Y.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 32
  • DOI: 10.1073/pnas.0502183102

An improved fit to Website osmotic pressure data
journal, September 1997


Adsorption of Hydrophobic Polyelectrolytes at Oppositely Charged Surfaces
journal, March 2002

  • Dobrynin, Andrey V.; Rubinstein, Michael
  • Macromolecules, Vol. 35, Issue 7
  • DOI: 10.1021/ma0114943

Microtubule orientation and spacing within bundles is critical for long-range kinesin-1 motility: Microtubule Bundles Architecture Affects Kinesin-1 Motility
journal, November 2014

  • Conway, Leslie; Gramlich, Michael W.; Ali Tabei, S. M.
  • Cytoskeleton, Vol. 71, Issue 11
  • DOI: 10.1002/cm.21197

Straight GDP-Tubulin Protofilaments Form in the Presence of Taxol
journal, October 2007


Asymptotic behavior and long-range interactions in aqueous solutions of poly(ethylene oxide)
journal, October 1991


    Works referencing / citing this record:

    Recent applications of synchrotron radiation and neutrons in the study of soft matter
    journal, February 2017


    D+ : software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures
    journal, February 2019


    A functional role for intrinsic disorder in the tau-tubulin complex
    journal, November 2016

    • Melo, Ana M.; Coraor, Juliana; Alpha-Cobb, Garrett
    • Proceedings of the National Academy of Sciences, Vol. 113, Issue 50
    • DOI: 10.1073/pnas.1610137113

    Independent tubulin binding and polymerization by the proline-rich region of Tau is regulated by Tau's N-terminal domain
    journal, November 2019

    • McKibben, Kristen M.; Rhoades, Elizabeth
    • Journal of Biological Chemistry, Vol. 294, Issue 50
    • DOI: 10.1074/jbc.ra119.010172

    Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes
    journal, November 2016

    • Niewidok, Benedikt; Igaev, Maxim; Sündermann, Frederik
    • Molecular Biology of the Cell, Vol. 27, Issue 22
    • DOI: 10.1091/mbc.e16-06-0402

    Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action
    journal, April 2016

    • Feinstein, H. Eric; Benbow, Sarah J.; LaPointe, Nichole E.
    • Journal of Neurochemistry, Vol. 137, Issue 6
    • DOI: 10.1111/jnc.13604

    Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences
    journal, March 2019

    • Melková, Kateřina; Zapletal, Vojtěch; Narasimhan, Subhash
    • Biomolecules, Vol. 9, Issue 3
    • DOI: 10.3390/biom9030105