Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

Kohl, Phillip A.; Song, Chaeyeon; Fletcher, Bretton J.; Best, Rebecca L.; Tchounwou, Christine; Garcia Arceo, Ximena; Chung, Peter J.; Miller, Herbert P.; Wilson, Leslie; Choi, Myung Chul; Li, Youli; Feinstein, Stuart C.; Safinya, Cyrus R.

doi:10.1038/s41467-024-46438-x

Title: Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

Abstract

Abstract The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg ²⁺ or Ca ²⁺ divalent cations in mixtures containing αβ-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (B _ws ), a transient intermediate MT bundle phase (B _int ), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau’s MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

Authors:

Kohl, Phillip A.; Song, Chaeyeon; Fletcher, Bretton J.;

; Tchounwou, Christine; Garcia Arceo, Ximena;

; Miller, Herbert P.; Wilson, Leslie; Choi, Myung Chul;

; Feinstein, Stuart C.;

Publication Date:: Fri Mar 15 00:00:00 EDT 2024

Sponsoring Org.:: USDOE

OSTI Identifier:: 2324692

Grant/Contract Number:: FG02-06ER46314

Resource Type:: Published Article

Journal Name:: Nature Communications

Additional Journal Information:: Journal Name: Nature Communications Journal Volume: 15 Journal Issue: 1; Journal ID: ISSN 2041-1723

Publisher:: Nature Publishing Group

Country of Publication:: United Kingdom

Language:: English

Citation Formats


                    Kohl, Phillip A., Song, Chaeyeon, Fletcher, Bretton J., Best, Rebecca L., Tchounwou, Christine, Garcia Arceo, Ximena, Chung, Peter J., Miller, Herbert P., Wilson, Leslie, Choi, Myung Chul, Li, Youli, Feinstein, Stuart C., and Safinya, Cyrus R. Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles.  United Kingdom: N. p., 2024. 
Web.  doi:10.1038/s41467-024-46438-x.

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                    Kohl, Phillip A., Song, Chaeyeon, Fletcher, Bretton J., Best, Rebecca L., Tchounwou, Christine, Garcia Arceo, Ximena, Chung, Peter J., Miller, Herbert P., Wilson, Leslie, Choi, Myung Chul, Li, Youli, Feinstein, Stuart C., & Safinya, Cyrus R. Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles.  United Kingdom.  https://doi.org/10.1038/s41467-024-46438-x

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                    Kohl, Phillip A., Song, Chaeyeon, Fletcher, Bretton J., Best, Rebecca L., Tchounwou, Christine, Garcia Arceo, Ximena, Chung, Peter J., Miller, Herbert P., Wilson, Leslie, Choi, Myung Chul, Li, Youli, Feinstein, Stuart C., and Safinya, Cyrus R. Fri .  
"Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles".  United Kingdom.  https://doi.org/10.1038/s41467-024-46438-x.

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@article{osti_2324692,

  title        = {Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles},

  author       = {Kohl, Phillip A. and Song, Chaeyeon and Fletcher, Bretton J. and Best, Rebecca L. and Tchounwou, Christine and Garcia Arceo, Ximena and Chung, Peter J. and Miller, Herbert P. and Wilson, Leslie and Choi, Myung Chul and Li, Youli and Feinstein, Stuart C. and Safinya, Cyrus R.},

  abstractNote = {Abstract The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg 2+ or Ca 2+ divalent cations in mixtures containing αβ-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (B ws ), a transient intermediate MT bundle phase (B int ), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau’s MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.},

  doi          = {10.1038/s41467-024-46438-x},

  journal      = {Nature Communications},

  number       = 1,

  volume       = 15,

  place        = {United Kingdom},

  year         = {Fri Mar 15 00:00:00 EDT 2024},

  month        = {Fri Mar 15 00:00:00 EDT 2024}

}

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Title: Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

Abstract

Citation Formats

Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization journal, June 2017

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

TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment journal, April 2019

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

Cell Movements: From Molecules to Motility book, January 2000

The MAP2/Tau family of microtubule-associated proteins journal, December 2004

Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment journal, July 2016

Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis journal, May 2008

Piecing Together Alzheimer's journal, December 2000

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

Tau Binds to Multiple Tubulin Dimers with Helical Structure journal, July 2015

MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton: quick-freeze, deep-etch immunoelectron microscopy and reconstitution studies journal, August 1988

Kinetic Stabilization of Microtubule Dynamics at Steady State by Tau and Microtubule-Binding Domains of Tau journal, September 1995

Evidence for two distinct binding sites for tau on microtubules journal, April 2004

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein journal, January 1994

Structure of growing microtubule ends: two-dimensional sheets close into tubes at variable rates journal, June 1995

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

Low resolution structure of microtubules in solution journal, July 1992

Structural changes accompanying GTP hydrolysis in microtubules: information from a slowly hydrolyzable analogue guanylyl-(alpha,beta)- methylene-diphosphonate journal, January 1995

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

Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner journal, January 2017

Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. journal, December 1995

The microtubule binding domain of tau protein journal, June 1989

Structural changes at microtubule ends accompanying GTP hydrolysis: Information from a slowly hydrolyzable analogue of GTP, guanylyl ( , )methylenediphosphonate journal, March 1998

Microtubule assembly, organization and dynamics in axons and dendrites journal, May 2009

Cell Biology by the Numbers book, December 2015

Microtubule Polymerization Dynamics journal, November 1997

The lattice as allosteric effector: Structural studies of - and -tubulin clarify the role of GTP in microtubule assembly journal, April 2008

The 72‐kDa Microtubule‐Associated Protein from Porcine Brain journal, April 1992

Historical Perspective book, January 2011

Nika : software for two-dimensional data reduction journal, March 2012

Hydrolysis of GTP associated with the formation of tubulin oligomers is involved in microtubule nucleation journal, July 1997

Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration journal, October 2011

Repeat motifs of tau bind to the insides of microtubules in the absence of taxol journal, January 2003

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

Nerve growth factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly-promoting factors journal, November 1985

Tau isoform–specific stabilization of intermediate states during microtubule assembly and disassembly journal, August 2019

Variations in the colchicine-binding domain provide insight into the structural switch of tubulin journal, August 2009

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

Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin journal, October 1977

Tau protein function in living cells. journal, December 1986

Small angle X-ray scattering edited by O. Glatter and O. Kratky journal, May 1983

Approximations Leading to a Unified Exponential/Power-Law Approach to Small-Angle Scattering journal, December 1995

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

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

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

High-Resolution Microtubule Structures Reveal the Structural Transitions in αβ-Tubulin upon GTP Hydrolysis journal, May 2014

Human Microtubule-Associated-Protein Tau Regulates the Number of Protofilaments in Microtubules: A Synchrotron X-Ray Scattering Study journal, July 2009

Near-atomic model of microtubule-tau interactions journal, May 2018

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

Altered microtubule organization in small-calibre axons of mice lacking tau protein journal, June 1994

The axon Hillock and the Initial Segment journal, July 1968

The axon initial segment and the maintenance of neuronal polarity journal, July 2010

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules journal, November 2015

Structure, Assembly, and Disassembly of Tubulin Single Rings journal, September 2018

Structural Change in FtsZ Induced by Intermolecular Interactions between Bound GTP and the T7 Loop journal, December 2013

Microtubule Organization in the Axon: TRIM46 Determines the Orientation journal, December 2015

Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau journal, March 1994

Polymer Physics book, June 2003

Expression and isolation of recombinant tau book, January 2017

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

TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays journal, December 2015

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

A collective motion description of tubulin βT7 loop dynamics journal, January 2019

Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules journal, January 2013

Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization
journal, June 2017

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

TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment
journal, April 2019

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

Cell Movements: From Molecules to Motility
book, January 2000

The MAP2/Tau family of microtubule-associated proteins
journal, December 2004

Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment
journal, July 2016

Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis
journal, May 2008

Piecing Together Alzheimer's
journal, December 2000

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

Tau Binds to Multiple Tubulin Dimers with Helical Structure
journal, July 2015

MAP2 is a component of crossbridges between microtubules and neurofilaments in the neuronal cytoskeleton: quick-freeze, deep-etch immunoelectron microscopy and reconstitution studies
journal, August 1988

Kinetic Stabilization of Microtubule Dynamics at Steady State by Tau and Microtubule-Binding Domains of Tau
journal, September 1995

Evidence for two distinct binding sites for tau on microtubules
journal, April 2004

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein
journal, January 1994

Structure of growing microtubule ends: two-dimensional sheets close into tubes at variable rates
journal, June 1995

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

Low resolution structure of microtubules in solution
journal, July 1992

Structural changes accompanying GTP hydrolysis in microtubules: information from a slowly hydrolyzable analogue guanylyl-(alpha,beta)- methylene-diphosphonate
journal, January 1995

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

Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner
journal, January 2017

Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules.
journal, December 1995

The microtubule binding domain of tau protein
journal, June 1989

Structural changes at microtubule ends accompanying GTP hydrolysis: Information from a slowly hydrolyzable analogue of GTP, guanylyl ( , )methylenediphosphonate
journal, March 1998

Microtubule assembly, organization and dynamics in axons and dendrites
journal, May 2009

Cell Biology by the Numbers
book, December 2015

Microtubule Polymerization Dynamics
journal, November 1997

The lattice as allosteric effector: Structural studies of - and -tubulin clarify the role of GTP in microtubule assembly
journal, April 2008

The 72‐kDa Microtubule‐Associated Protein from Porcine Brain
journal, April 1992

Historical Perspective
book, January 2011

Nika : software for two-dimensional data reduction
journal, March 2012

Hydrolysis of GTP associated with the formation of tubulin oligomers is involved in microtubule nucleation
journal, July 1997

Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration
journal, October 2011

Repeat motifs of tau bind to the insides of microtubules in the absence of taxol
journal, January 2003

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

Nerve growth factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly-promoting factors
journal, November 1985

Tau isoform–specific stabilization of intermediate states during microtubule assembly and disassembly
journal, August 2019

Variations in the colchicine-binding domain provide insight into the structural switch of tubulin
journal, August 2009

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

Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin
journal, October 1977

Tau protein function in living cells.
journal, December 1986

Small angle X-ray scattering edited by O. Glatter and O. Kratky
journal, May 1983

Approximations Leading to a Unified Exponential/Power-Law Approach to Small-Angle Scattering
journal, December 1995

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

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

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

High-Resolution Microtubule Structures Reveal the Structural Transitions in αβ-Tubulin upon GTP Hydrolysis
journal, May 2014

Human Microtubule-Associated-Protein Tau Regulates the Number of Protofilaments in Microtubules: A Synchrotron X-Ray Scattering Study
journal, July 2009

Near-atomic model of microtubule-tau interactions
journal, May 2018

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

Altered microtubule organization in small-calibre axons of mice lacking tau protein
journal, June 1994

The axon Hillock and the Initial Segment
journal, July 1968

The axon initial segment and the maintenance of neuronal polarity
journal, July 2010

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules
journal, November 2015

Structure, Assembly, and Disassembly of Tubulin Single Rings
journal, September 2018

Structural Change in FtsZ Induced by Intermolecular Interactions between Bound GTP and the T7 Loop
journal, December 2013

Microtubule Organization in the Axon: TRIM46 Determines the Orientation
journal, December 2015

Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau
journal, March 1994

Polymer Physics
book, June 2003

Expression and isolation of recombinant tau
book, January 2017

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

TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays
journal, December 2015

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

A collective motion description of tubulin βT7 loop dynamics
journal, January 2019

Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules
journal, January 2013