Hallmarks of molecular action of microtubule stabilizing agents

Effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation

Marina Khrapunovich-Baine, Vilas Menon, Chia-Ping H. Yang, Peter T. Northcote, John H. Miller, Ruth Hogue Angeletti, Andras Fiser, Susan Band Horwitz, Hui Xiao

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Microtubule stabilizing agents (MSAs) comprise a class of drugs that bind to microtubule (MT) polymers and stabilize them against disassembly. Several of these agents are currently in clinical use as anticancer drugs, whereas others are in various stages of development. Nonetheless, there is insufficient knowledge about the molecular modes of their action. Recent studies from our laboratory utilizing hydrogen-deuterium exchange in combination with mass spectrometry (MS) provide new information on the conformational effects of Taxol and discodermolide on microtubules isolated from chicken erythrocytes (CET).Wereport here a comprehensive analysis of the effects of epothilone B, ixabepilone (IXEMPRA™), laulimalide, and peloruside A on CET conformation. The results of our comparative hydrogen-deuterium exchange MS studies indicate that all MSAs have significant conformational effects on the C-terminal H12 helix of α-tubulin, which is a likely molecular mechanism for the previously observed modulations of MT interactions with microtubule-associated and motor proteins. More importantly, the major mode of MT stabilization by MSAs is the tightening of the longitudinal interactions between two adjacent αβ-tubulin heterodimers at the interdimer interface. In contrast to previous observations reported with bovine brain tubulin, the lateral interactions between the adjacent protofilaments in CET are particularly strongly stabilized by peloruside A and laulimalide, drugs that bind outside the taxane site. This not only highlights the significance of tubulin isotype composition in modulating drug effects on MT conformation and stability but also provides a potential explanation for the synergy observed when combinations of taxane and alternative site binding drugs are used.

Original languageEnglish (US)
Pages (from-to)11765-11778
Number of pages14
JournalJournal of Biological Chemistry
Volume286
Issue number13
DOIs
StatePublished - Apr 1 2011

Fingerprint

Excipients
Microtubules
Conformations
Tubulin
Pharmaceutical Preparations
Deuterium
Mass spectrometry
Hydrogen
Chickens
Erythrocytes
Mass Spectrometry
Paclitaxel
Brain
Polymers
Stabilization
Microtubule-Associated Proteins
Binding Sites
Modulation
ixabepilone
laulimalide

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hallmarks of molecular action of microtubule stabilizing agents : Effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation. / Khrapunovich-Baine, Marina; Menon, Vilas; Yang, Chia-Ping H.; Northcote, Peter T.; Miller, John H.; Angeletti, Ruth Hogue; Fiser, Andras; Band Horwitz, Susan; Xiao, Hui.

In: Journal of Biological Chemistry, Vol. 286, No. 13, 01.04.2011, p. 11765-11778.

Research output: Contribution to journalArticle

Khrapunovich-Baine, Marina ; Menon, Vilas ; Yang, Chia-Ping H. ; Northcote, Peter T. ; Miller, John H. ; Angeletti, Ruth Hogue ; Fiser, Andras ; Band Horwitz, Susan ; Xiao, Hui. / Hallmarks of molecular action of microtubule stabilizing agents : Effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 13. pp. 11765-11778.
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