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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 Laboratory (SLAC), 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.
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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. https://doi.org/10.1073/pnas.1513172112
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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. https://doi.org/10.1073/pnas.1513172112.
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@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 = {Thu Nov 05 00:00:00 EST 2015},
month = {Thu Nov 05 00:00:00 EST 2015}
}
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