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Title: Inhibition of Microtubule Depolymerization by Osmolytes

Abstract

Microtubule dynamics play a critical role in the normal physiology of eukaryotic cells as well as a number of cancers and neurodegenerative disorders. The polymerization/depolymerization of microtubules is regulated by a variety of stabilizing and destabilizing factors, including microtubule-associated proteins and therapeutic agents (e.g., paclitaxel, nocodazole). Here in this paper, we describe the ability of the osmolytes polyethylene glycol (PEG) and trimethylamine-N-oxide (TMAO) to inhibit the depolymerization of individual microtubule filaments for extended periods of time (up to 30 days). We further show that PEG stabilizes microtubules against both temperature- and calcium-induced depolymerization. Our results collectively suggest that the observed inhibition may be related to combination of the kosmotropic behavior and excluded volume/osmotic pressure effects associated with PEG and TMAO. Lastly, taken together with prior studies, our data suggest that the physiochemical properties of the local environment can regulate microtubule depolymerization and may potentially play an important role in in vivo microtubule dynamics.

Authors:
 [1];  [1];  [1];  [1];  [1]
  1. Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Center for Integrated Nanotechnologies
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Materials Sciences & Engineering Division; USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1441461
Report Number(s):
SAND-2018-5036J
Journal ID: ISSN 1525-7797; 662993
Grant/Contract Number:  
AC04-94AL85000; NA0003525
Resource Type:
Accepted Manuscript
Journal Name:
Biomacromolecules
Additional Journal Information:
Journal Volume: 19; Journal Issue: 7; Journal ID: ISSN 1525-7797
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Bachand, George D., Jain, Rishi, Ko, Randy, Bouxsein, Nathan F., and VanDelinder, Virginia. Inhibition of Microtubule Depolymerization by Osmolytes. United States: N. p., 2018. Web. doi:10.1021/acs.biomac.7b01799.
Bachand, George D., Jain, Rishi, Ko, Randy, Bouxsein, Nathan F., & VanDelinder, Virginia. Inhibition of Microtubule Depolymerization by Osmolytes. United States. https://doi.org/10.1021/acs.biomac.7b01799
Bachand, George D., Jain, Rishi, Ko, Randy, Bouxsein, Nathan F., and VanDelinder, Virginia. Tue . "Inhibition of Microtubule Depolymerization by Osmolytes". United States. https://doi.org/10.1021/acs.biomac.7b01799. https://www.osti.gov/servlets/purl/1441461.
@article{osti_1441461,
title = {Inhibition of Microtubule Depolymerization by Osmolytes},
author = {Bachand, George D. and Jain, Rishi and Ko, Randy and Bouxsein, Nathan F. and VanDelinder, Virginia},
abstractNote = {Microtubule dynamics play a critical role in the normal physiology of eukaryotic cells as well as a number of cancers and neurodegenerative disorders. The polymerization/depolymerization of microtubules is regulated by a variety of stabilizing and destabilizing factors, including microtubule-associated proteins and therapeutic agents (e.g., paclitaxel, nocodazole). Here in this paper, we describe the ability of the osmolytes polyethylene glycol (PEG) and trimethylamine-N-oxide (TMAO) to inhibit the depolymerization of individual microtubule filaments for extended periods of time (up to 30 days). We further show that PEG stabilizes microtubules against both temperature- and calcium-induced depolymerization. Our results collectively suggest that the observed inhibition may be related to combination of the kosmotropic behavior and excluded volume/osmotic pressure effects associated with PEG and TMAO. Lastly, taken together with prior studies, our data suggest that the physiochemical properties of the local environment can regulate microtubule depolymerization and may potentially play an important role in in vivo microtubule dynamics.},
doi = {10.1021/acs.biomac.7b01799},
journal = {Biomacromolecules},
number = 7,
volume = 19,
place = {United States},
year = {2018},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 14 works
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Figures / Tables:

Figure 1 Figure 1: Figure 1. (a) Fluorescence photomicrographs of microtubule stabilized with PEG600 or paclitaxel at various time intervals over the course of 30 days. (b) Number of microtubules per mm2 and (c) microtubule length over time for samples stabilized with PEG600 (■) or paclitaxel (⃞ ). Error bars = standardmore » deviation. Scale bars = 15 μm.« less

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Works referenced in this record:

The osmotic pressure of concentrated protein solutions: Effect of concentration and ph in saline solutions of bovine serum albumin
journal, February 1981

  • Vilker, Vincent L.; Colton, Clark K.; Smith, Kenneth A.
  • Journal of Colloid and Interface Science, Vol. 79, Issue 2
  • DOI: 10.1016/0021-9797(81)90106-5

Modulation of the Polymerization Kinetics of α/β-Tubulin by Osmolytes and Macromolecular Crowding
journal, January 2017

  • Schummel, Paul Hendrik; Gao, Mimi; Winter, Roland
  • ChemPhysChem, Vol. 18, Issue 2
  • DOI: 10.1002/cphc.201700002

Directed self-assembly of 1D microtubule nano-arrays
journal, January 2014

  • Bachand, M.; Bouxsein, N. F.; Cheng, S.
  • RSC Adv., Vol. 4, Issue 97
  • DOI: 10.1039/C4RA11765D

Trimethylamine N -oxide stabilizes proteins via a distinct mechanism compared with betaine and glycine
journal, February 2017

  • Liao, Yi-Ting; Manson, Anthony C.; DeLyser, Michael R.
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 10
  • DOI: 10.1073/pnas.1614609114

Natural osmolyte trimethylamine N-oxide stimulates tubulin polymerization and reverses urea inhibition
journal, August 1997


Interactions regulating the head-to-tail directed assembly of biological Janus rods
journal, January 2017

  • Greene, A. C.; Bachand, M.; Gomez, A.
  • Chemical Communications, Vol. 53, Issue 32
  • DOI: 10.1039/C7CC01566F

Effects of Macromolecular Crowding on the Structure of a Protein Complex: A Small-Angle Scattering Study of Superoxide Dismutase
journal, February 2015

  • Rajapaksha, Ajith; Stanley, Christopher B.; Todd, Brian A.
  • Biophysical Journal, Vol. 108, Issue 4
  • DOI: 10.1016/j.bpj.2014.12.046

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


Effects of osmotic force and torque on microtubule bundling and pattern formation
journal, October 2008


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

Natural Methylamine Osmolytes, Trimethylamine N-Oxide and Betaine, Increase Tau-Induced Polymerization of Microtubules
journal, September 1998

  • Tseng, Huang-Chun; Graves, Donald J.
  • Biochemical and Biophysical Research Communications, Vol. 250, Issue 3
  • DOI: 10.1006/bbrc.1998.9382

The Stability and Functionality of Chemically Crosslinked Microtubules
journal, June 2006


How calcium causes microtubule depolymerization
journal, January 1997


Macromolecular crowding: obvious but underappreciated
journal, October 2001


Kosmotropes Form the Basis of Protein-Resistant Surfaces
journal, March 2003

  • Kane, Ravi S.; Deschatelets, Pascal; Whitesides, George M.
  • Langmuir, Vol. 19, Issue 6
  • DOI: 10.1021/la020737x

Microtubule dynamics and microtubule caps: a time-resolved cryo- electron microscopy study
journal, September 1991


Single Filament Behavior of Microtubules in the Presence of Added Divalent Counterions
journal, September 2014

  • Bouxsein, Nathan F.; Bachand, George D.
  • Biomacromolecules, Vol. 15, Issue 10
  • DOI: 10.1021/bm500988r

Neurodegeneration and microtubule dynamics: death by a thousand cuts
journal, September 2015

  • Dubey, Jyoti; Ratnakaran, Neena; Koushika, Sandhya P.
  • Frontiers in Cellular Neuroscience, Vol. 9
  • DOI: 10.3389/fncel.2015.00343

Microtubule-binding agents: a dynamic field of cancer therapeutics
journal, October 2010

  • Dumontet, Charles; Jordan, Mary Ann
  • Nature Reviews Drug Discovery, Vol. 9, Issue 10
  • DOI: 10.1038/nrd3253

Microtubule Polymerization Dynamics
journal, November 1997


Building the Neuronal Microtubule Cytoskeleton
journal, August 2015


Microscopic insights into the protein-stabilizing effect of trimethylamine N-oxide (TMAO)
journal, May 2014

  • Ma, J.; Pazos, I. M.; Gai, F.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 23
  • DOI: 10.1073/pnas.1403224111

Thermodynamic and structural analysis of microtubule assembly: the role of GTP hydrolysis
journal, March 1997


How does solvation in the cell affect protein folding and binding?
journal, February 2018

  • Davis, Caitlin M.; Gruebele, Martin; Sukenik, Shahar
  • Current Opinion in Structural Biology, Vol. 48
  • DOI: 10.1016/j.sbi.2017.09.003

Dynamics and mechanics of the microtubule plus end
journal, April 2003


Macromolecular crowding gives rise to microviscosity, anomalous diffusion and accelerated actin polymerization
journal, April 2015


Molecular Mechanism for the Preferential Exclusion of TMAO from Protein Surfaces
journal, October 2012

  • Canchi, Deepak R.; Jayasimha, Pruthvi; Rau, Donald C.
  • The Journal of Physical Chemistry B, Vol. 116, Issue 40
  • DOI: 10.1021/jp304298c

Weak protein–protein interactions in live cells are quantified by cell-volume modulation
journal, June 2017

  • Sukenik, Shahar; Ren, Pin; Gruebele, Martin
  • Proceedings of the National Academy of Sciences
  • DOI: 10.1073/pnas.1700818114

Non-linear effects of macromolecular crowding on enzymatic activity of multi-copper oxidase
journal, April 2010

  • Pozdnyakova, Irina; Wittung-Stafshede, Pernilla
  • Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1804, Issue 4
  • DOI: 10.1016/j.bbapap.2009.11.013

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


Insights into the mechanism of microtubule stabilization by Taxol
journal, June 2006

  • Xiao, H.; Verdier-Pinard, P.; Fernandez-Fuentes, N.
  • Proceedings of the National Academy of Sciences, Vol. 103, Issue 27
  • DOI: 10.1073/pnas.0603704103

Dynamic instability of microtubule growth
journal, November 1984

  • Mitchison, Tim; Kirschner, Marc
  • Nature, Vol. 312, Issue 5991
  • DOI: 10.1038/312237a0

Kosmotrope-like Hydration Behavior of Polyethylene Glycol from Microcalorimetry and Binding Isotherm Measurements
journal, February 2013

  • Chen, Wen-Yih; Hsu, Min-Yen; Tsai, Ching-Wei
  • Langmuir, Vol. 29, Issue 13
  • DOI: 10.1021/la304500w

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


The macromolecular crowding effect – from in vitro into the cell
journal, January 2016


Understanding microtubule dynamics for improved cancer therapy
journal, November 2005

  • Honore, S.; Pasquier, E.; Braguer, D.
  • Cellular and Molecular Life Sciences, Vol. 62, Issue 24
  • DOI: 10.1007/s00018-005-5330-x

Macromolecular crowding: effects on actin polymerisation
journal, May 1997


Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability
journal, December 2004


Beyond the Excluded Volume Effects: Mechanistic Complexity of the Crowded Milieu
journal, January 2015


Temperature-dependent reversible assembly of taxol-treated microtubules.
journal, December 1987


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


Effect of temperature and pressure on polymerisation equilibrium of neuronal microtubules
journal, February 1976

  • Engelborghs, Yves; Heremans, Karel A. H.; De Maeyer, Leo C. M.
  • Nature, Vol. 259, Issue 5545
  • DOI: 10.1038/259686a0

Nonneuronal isoforms of STOP protein are responsible for microtubule cold stability in mammalian fibroblasts
journal, May 1998

  • Denarier, E.; Fourest-Lieuvin, A.; Bosc, C.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 11
  • DOI: 10.1073/pnas.95.11.6055

Catastrophic depolymerization of microtubules driven by subunit shape change
journal, January 2018

  • Bollinger, Jonathan A.; Stevens, Mark J.
  • Soft Matter, Vol. 14, Issue 10
  • DOI: 10.1039/C7SM02033C

Microtubule-dependent Oligomerization of Tau: IMPLICATIONS FOR PHYSIOLOGICAL TAU FUNCTION AND TAUOPATHIES
journal, June 2003

  • Makrides, Victoria; Shen, Ting E.; Bhatia, Rajinder
  • Journal of Biological Chemistry, Vol. 278, Issue 35
  • DOI: 10.1074/jbc.M305207200

Imperfect crowding adaptation of mammalian cells towards osmotic stress and its modulation by osmolytes
journal, January 2017

  • Gnutt, David; Brylski, Oliver; Edengeiser, Eugen
  • Molecular BioSystems, Vol. 13, Issue 11
  • DOI: 10.1039/C7MB00432J

Macromolecular Crowding Pushes Catalyzed Microtubule Growth to Near the Theoretical Limit
journal, July 2013

  • Wieczorek, Michal; Chaaban, Sami; Brouhard, Gary J.
  • Cellular and Molecular Bioengineering, Vol. 6, Issue 4
  • DOI: 10.1007/s12195-013-0292-9

Purification of brain tubulin through two cycles of polymerization–depolymerization in a high-molarity buffer
journal, November 2003


Structure of the αβ tubulin dimer by electron crystallography
journal, January 1998

  • Nogales, Eva; Wolf, Sharon G.; Downing, Kenneth H.
  • Nature, Vol. 391, Issue 6663
  • DOI: 10.1038/34465

The Role of the Cytoskeleton in Volume Regulation and Beading Transitions in PC12 Neurites
journal, December 2010


Kinesin Takes One 8-nm Step for Each ATP That It Hydrolyzes
journal, February 1999

  • Coy, David L.; Wagenbach, Michael; Howard, Jonathon
  • Journal of Biological Chemistry, Vol. 274, Issue 6
  • DOI: 10.1074/jbc.274.6.3667

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


Molecular-crowding effects on single-molecule RNA folding/unfolding thermodynamics and kinetics
journal, May 2014

  • Dupuis, N. F.; Holmstrom, E. D.; Nesbitt, D. J.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 23
  • DOI: 10.1073/pnas.1316039111

Mechanism of microtubule depolymerization. Correlation of rapid induced disassembly experiments with a kinetic model for endwise depolymerization.
journal, September 1980


Works referencing / citing this record:

Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation
journal, January 2020

  • Kushwah, Neetu; Jain, Vishal; Yadav, Dhananjay
  • Biomolecules, Vol. 10, Issue 1
  • DOI: 10.3390/biom10010132

The Microbial Metabolite Trimethylamine N-Oxide Links Vascular Dysfunctions and the Autoimmune Disease Rheumatoid Arthritis
journal, August 2019

  • Chan, Marion M.; Yang, Xiaofeng; Wang, Hong
  • Nutrients, Vol. 11, Issue 8
  • DOI: 10.3390/nu11081821

Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation
journal, January 2020

  • Kushwah, Neetu; Jain, Vishal; Yadav, Dhananjay
  • Biomolecules, Vol. 10, Issue 1
  • DOI: 10.3390/biom10010132

The Microbial Metabolite Trimethylamine N-Oxide Links Vascular Dysfunctions and the Autoimmune Disease Rheumatoid Arthritis
journal, August 2019

  • Chan, Marion M.; Yang, Xiaofeng; Wang, Hong
  • Nutrients, Vol. 11, Issue 8
  • DOI: 10.3390/nu11081821

Anticancer and antibacterial activity in vitro evaluation of iridium(III) polypyridyl complexes
journal, December 2018

  • Yi, Qiao-Yan; Zhang, Wen-Yao; He, Miao
  • JBIC Journal of Biological Inorganic Chemistry, Vol. 24, Issue 2
  • DOI: 10.1007/s00775-018-1635-8

Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.