Tubulin CFEOM mutations both inhibit or activate kinesin motor activity
Date
2024-03-01
Authors
Luchniak, Anna
Roy, Pallavi Sinha
Kumar, Ambuj
Gelfand, Vladimir I.
Jernigan, Robert L.
Gupta, Mohan L.
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American Society for Cell Biology
Abstract
Kinesin-mediated transport along microtubules is critical for axon development and health. Mutations in the kinesin Kif21a, or the microtubule subunit β-tubulin, inhibit axon growth and/or maintenance resulting in the eye-movement disorder congenital fibrosis of the extraocular muscles (CFEOM). While most examined CFEOM-causing β-tubulin mutations inhibit kinesin–microtubule interactions, Kif21a mutations activate the motor protein. These contrasting observations have led to opposed models of inhibited or hyperactive Kif21a in CFEOM. We show that, contrary to other CFEOM-causing β-tubulin mutations, R380C enhances kinesin activity. Expression of β-tubulin-R380C increases kinesin-mediated peroxisome transport in S2 cells. The binding frequency, percent motile engagements, run length and plus-end dwell time of Kif21a are also elevated on β-tubulin-R380C compared with wildtype microtubules in vitro. This conserved effect persists across tubulins from multiple species and kinesins from different families. The enhanced activity is independent of tail-mediated kinesin autoinhibition and thus utilizes a mechanism distinct from CFEOM-causing Kif21a mutations. Using molecular dynamics, we visualize how β-tubulin-R380C allosterically alters critical structural elements within the kinesin motor domain, suggesting a basis for the enhanced motility. These findings resolve the disparate models and confirm that inhibited or increased kinesin activity can both contribute to CFEOM. They also demonstrate the microtubule’s role in regulating kinesins and highlight the importance of balanced transport for cellular and organismal health.
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This article is published as Luchniak, Anna, Pallavi Sinha Roy, Ambuj Kumar, Ian C. Schneider, Vladimir I. Gelfand, Robert L. Jernigan, and Mohan L. Gupta Jr. "Tubulin CFEOM mutations both inhibit or activate kinesin motor activity." Molecular Biology of the Cell 35, no. 3 (2024): ar32. doi: https://doi.org/10.1091/mbc.E23-01-0020. © 2024 Luchniak et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication, it is available to the public under an Attribution–Noncommercial–Share Alike 4.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/4.0).