Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 21, Pages 10366-10371Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1900441116
Keywords
cryo-EM; MD; tubulin modifications; microtubule; acetylation
Categories
Funding
- University of California
- San Francisco-University of California
- Berkeley Sackler Faculty Exchange Program
- National Institute of General Medical Sciences (NIGMS) [R01-GM123159]
- NIGMS [R35-GM127018, P01-GM063210]
- National Science Foundation [2016222703]
- National Academy of Sciences National Research Council Ford Foundation Grant
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Acetylation of K40 in alpha-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 alpha TAT1-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 alpha K40. Modification of alpha K40 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.
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