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 »
- 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.
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
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.
@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}
}
https://doi.org/10.1073/pnas.1513172112
Web of Science
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