Structural evidence for cooperative microtubule stabilization by taxol and the endogenous dynamics regulator MAP4

Hui Xiao, Hui Wang, Xuechun Zhang, Zongcai Tu, Chloë Bulinski, Marina Khrapunovich-Baine, Ruth Hogue Angeletti, Susan Band Horwitz

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24 Scopus citations

Abstract

Microtubules (MTs) composed of αβ-tubulin heterodimers are highly dynamic polymers, whose stability can be regulated by numerous endogenous and exogenous factors. Both the antimitotic drug Taxol and microtubule- associated proteins (MAPs) stabilize this dynamicity by binding to and altering the conformation of MTs. In the current study, amide hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) was used to examine the structural and dynamic properties of the MT complex with the microtubule binding domain of MAP4 (MTB-MAP4) in the presence and absence of Taxol. The changes in the HDX levels indicate that MTB-MAP4 may bind to both the outside and the luminal surfaces of the MTs and that Taxol reduces both of these interactions. The MTB-MAP4 binding induces conformational rearrangements of α- and β-tubulin that promote an overall stabilization of MTs. Paradoxically, despite Taxol's negative effects on MAP4 interactions with the MTs, its binding to the MTB-MAP4-MT complex further reduces the overall deuterium incorporation, suggesting that a more stable complex is formed in the presence of the drug.

Original languageEnglish (US)
Pages (from-to)744-752
Number of pages9
JournalACS Chemical Biology
Volume7
Issue number4
DOIs
StatePublished - Apr 20 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Xiao, H., Wang, H., Zhang, X., Tu, Z., Bulinski, C., Khrapunovich-Baine, M., Hogue Angeletti, R., & Horwitz, S. B. (2012). Structural evidence for cooperative microtubule stabilization by taxol and the endogenous dynamics regulator MAP4. ACS Chemical Biology, 7(4), 744-752. https://doi.org/10.1021/cb200403x