The microtubule-severing protein UNC-45A preferentially binds to curved microtubules and counteracts the microtubule-straightening effects of Taxol.

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Microtubules*/metabolism ; Paclitaxel*/pharmacology ; Paclitaxel*/metabolism ; Intracellular Signaling Peptides and Proteins*/metabolism; Microfilament Proteins/metabolism ; Microtubule Proteins/metabolism ; Molecular Chaperones/metabolism
    • Abstract:
      Uncoordinated protein 45A (UNC-45A) is the only known ATP-independent microtubule (MT)-severing protein. Thus, it severs MTs via a novel mechanism. In vitro and in cells, UNC-45A-mediated MT severing is preceded by the appearance of MT bends. While MTs are stiff biological polymers, in cells, they often curve, and the result of this curving can be breaking off. The contribution of MT-severing proteins on MT lattice curvature is largely undefined. Here, we show that UNC-45A curves MTs. Using in vitro biophysical reconstitution and total internal fluorescence microscopy analysis, we show that UNC-45A is enriched in the areas where MTs are curved versus the areas where MTs are straight. In cells, we show that UNC-45A overexpression increases MT curvature and its depletion has the opposite effect. We also show that this effect occurs is independent of actomyosin contractility. Lastly, we show for the first time that in cells, Paclitaxel straightens MTs, and that UNC-45A can counteracts the MT-straightening effects of the drug.
      Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
      (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Comments:
      Update of: bioRxiv. 2023 Sep 13:2023.09.12.557417. doi: 10.1101/2023.09.12.557417. (PMID: 37745537)
    • Grant Information:
      R01 GM130800 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: UNC-45A; microtubule curvature; microtubules
    • Accession Number:
      0 (Microfilament Proteins)
      0 (Microtubule Proteins)
      0 (Molecular Chaperones)
      P88XT4IS4D (Paclitaxel)
      0 (Intracellular Signaling Peptides and Proteins)
    • Publication Date:
      Date Created: 20231020 Date Completed: 20231129 Latest Revision: 20240624
    • Publication Date:
      20240624
    • Accession Number:
      PMC10654038
    • Accession Number:
      10.1016/j.jbc.2023.105355
    • Accession Number:
      37858676