Dual Impact of a Benzimidazole Resistant β-Tubulin on Microtubule Behavior in Fission Yeast

Mamika Minagawa, Minamo Shirato, Mika Toya, Masamitsu Sato

Research output: Contribution to journalArticlepeer-review

Abstract

The cytoskeleton microtubule consists of polymerized αβ-tubulin dimers and plays essential roles in many cellular events. Reagents that inhibit microtubule behaviors have been developed as antifungal, antiparasitic, and anticancer drugs. Benzimidazole compounds, including thiabendazole (TBZ), carbendazim (MBC), and nocodazole, are prevailing microtubule poisons that target β-tubulin and inhibit microtubule polymerization. The molecular basis, however, as to how the drug acts on β-tubulin remains controversial. Here, we characterize the S. pombe β-tubulin mutant nda3-TB101, which was previously isolated as a mutant resistance to benzimidazole. The mutation site tyrosine at position 50 is located in the interface of two lateral β-tubulin proteins and at the gate of a putative binging pocket for benzimidazole. Our observation revealed two properties of the mutant tubulin. First, the dynamics of cellular microtubules comprising the mutant β-tubulin were stabilized in the absence of benzimidazole. Second, the mutant protein reduced the affinity to benzimidazole in vitro. We therefore conclude that the mutant β-tubulin Nda3-TB101 exerts a dual effect on microtubule behaviors: the mutant β-tubulin stabilizes microtubules and is insensitive to benzimidazole drugs. This notion fine-tunes the current elusive molecular model regarding binding of benzimidazole to β-tubulin.

Original languageEnglish
JournalCells
Volume10
Issue number5
DOIs
Publication statusPublished - 2021 Apr 28

Keywords

  • benzimidazole
  • cytoskeleton
  • fission yeast
  • fungicides
  • microtubules
  • tubulin

ASJC Scopus subject areas

  • Medicine(all)

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