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ACS Chem Biol. 2012 Apr 20;7(4):744-52. doi: 10.1021/cb200403x. Epub 2012 Feb 6.

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

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1
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.

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.

PMID:
22270553
PMCID:
PMC3804043
DOI:
10.1021/cb200403x
[Indexed for MEDLINE]
Free PMC Article
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