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Title: Effects of α-tubulin acetylation on microtubule structure and stability

Abstract

Acetylation of K40 in α-tubulin is the sole posttranslational modification to mark the luminal surface of microtubules. It is still controversial whether its relationship with microtubule stabilization is correlative or causative. We have obtained high-resolution cryo-electron microscopy (cryo-EM) reconstructions of pure samples of αTAT1-acetylated and SIRT2-deacetylated microtubules to visualize the structural consequences of this modification and reveal its potential for influencing the larger assembly properties of microtubules. We modeled the conformational ensembles of the unmodified and acetylated states by using the experimental cryo-EM density as a structural restraint in molecular dynamics simulations. We found that acetylation alters the conformational landscape of the flexible loop that contains αK40. Modification of αK40 reduces the disorder of the loop and restricts the states that it samples. We propose that the change in conformational sampling that we describe, at a location very close to the lateral contacts site, is likely to affect microtubule stability and function.

Authors:
 [1];  [2];  [3]; ORCiD logo [4];  [1];  [5];  [5];  [6];  [7]; ORCiD logo [8]
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  1. Univ. of California, Berkeley, CA (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Washington Univ., St. Louis, MO (United States)
  3. Univ. of California, San Francisco, CA (United States); Univ. Montpellier, Montpellier (France)
  4. Univ. of California, San Francisco, CA (United States)
  5. Univ. of Cambridge, Cambridge (United Kingdom)
  6. Univ. of Cambridge, Cambridge (United Kingdom); Inst. Pasteur, Paris (France)
  7. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, San Francisco, CA (United States)
  8. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Science Foundation (NSF); National Institute of General Medical Sciences (NIGMS); National Academy of Sciences National Research Council Ford Foundation
OSTI Identifier:
1559217
Grant/Contract Number:  
AC02-05CH11231; 2016222703; R01-GM123159; R35-GM127018; P01-GM063210
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 21; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; cryo-EM; MD; tubulin modifications; microtubule; acetylation

Citation Formats

Eshun-Wilson, Lisa, Zhang, Rui, Portran, Didier, Nachury, Maxence V., Toso, Daniel B., Löhr, Thomas, Vendruscolo, Michele, Bonomi, Massimiliano, Fraser, James S., and Nogales, Eva. Effects of α-tubulin acetylation on microtubule structure and stability. United States: N. p., 2019. Web. doi:10.1073/pnas.1900441116.
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Eshun-Wilson, Lisa, Zhang, Rui, Portran, Didier, Nachury, Maxence V., Toso, Daniel B., Löhr, Thomas, Vendruscolo, Michele, Bonomi, Massimiliano, Fraser, James S., & Nogales, Eva. Effects of α-tubulin acetylation on microtubule structure and stability. United States. doi:10.1073/pnas.1900441116.
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Eshun-Wilson, Lisa, Zhang, Rui, Portran, Didier, Nachury, Maxence V., Toso, Daniel B., Löhr, Thomas, Vendruscolo, Michele, Bonomi, Massimiliano, Fraser, James S., and Nogales, Eva. Thu . "Effects of α-tubulin acetylation on microtubule structure and stability". United States. doi:10.1073/pnas.1900441116. https://www.osti.gov/servlets/purl/1559217.
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@article{osti_1559217,
title = {Effects of α-tubulin acetylation on microtubule structure and stability},
author = {Eshun-Wilson, Lisa and Zhang, Rui and Portran, Didier and Nachury, Maxence V. and Toso, Daniel B. and Löhr, Thomas and Vendruscolo, Michele and Bonomi, Massimiliano and Fraser, James S. and Nogales, Eva},
abstractNote = {Acetylation of K40 in α-tubulin is the sole posttranslational modification to mark the luminal surface of microtubules. It is still controversial whether its relationship with microtubule stabilization is correlative or causative. We have obtained high-resolution cryo-electron microscopy (cryo-EM) reconstructions of pure samples of αTAT1-acetylated and SIRT2-deacetylated microtubules to visualize the structural consequences of this modification and reveal its potential for influencing the larger assembly properties of microtubules. We modeled the conformational ensembles of the unmodified and acetylated states by using the experimental cryo-EM density as a structural restraint in molecular dynamics simulations. We found that acetylation alters the conformational landscape of the flexible loop that contains αK40. Modification of αK40 reduces the disorder of the loop and restricts the states that it samples. We propose that the change in conformational sampling that we describe, at a location very close to the lateral contacts site, is likely to affect microtubule stability and function.},
doi = {10.1073/pnas.1900441116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 21,
volume = 116,
place = {United States},
year = {2019},
month = {5}
}
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DOI:  10.1073/pnas.1900441116
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