title: Structural evidence for cooperative microtubule stabilization by Taxol and the endogenous dynamics regulator MAP4.
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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Xuechun
authors.initials: X
authors.lastname: Zhang
authors.forename: Zongcai
authors.initials: Z
authors.lastname: Tu
authors.forename: Chloë
authors.initials: C
authors.lastname: Bulinski
authors.forename: Marina
authors.initials: M
authors.lastname: Khrapunovich-Baine
authors.forename: Ruth
authors.initials: R
authors.lastname: Hogue Angeletti
authors.forename: Susan Band
authors.initials: SB
authors.lastname: Horwitz
mesh_terms: D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry*; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects
chemical_list: D008869:Microtubule-Associated Proteins; D017239:Paclitaxel