Acidic pH promotes oligomerization and membrane insertion of the BclXL apoptotic repressor

Vikas Bhat, Dmitry Kurouski, Max B. Olenick, Caleb B. McDonald, David C. Mikles, Brian J. Deegan, Kenneth L. Seldeen, Igor K. Lednev, Amjad Farooq

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8 Scopus citations

Abstract

Solution pH is believed to serve as an intricate regulatory switch in the induction of apoptosis central to embryonic development and cellular homeostasis. Herein, using an array of biophysical techniques, we provide evidence that acidic pH promotes the assembly of BclXL apoptotic repressor into a megadalton oligomer with a plume-like appearance and harboring structural features characteristic of a molten globule. Strikingly, our data reveal that pH tightly modulates not only oligomerization but also ligand binding and membrane insertion of BclXL in a highly subtle manner. Thus, while oligomerization and the accompanying molten globular content of BclXL is least favorable at pH 6, both of these structural features become more pronounced under acidic and alkaline conditions. However, membrane insertion of BclXL appears to be predominantly favored under acidic conditions. In a remarkable contrast, while ligand binding to BclXL optimally occurs at pH 6, it is diminished by an order of magnitude at lower and higher pH. This reciprocal relationship between BclXL oligomerization and ligand binding lends new insights into how pH modulates functional versatility of a key apoptotic regulator and strongly argues that the molten globule may serve as an intermediate primed for membrane insertion in response to apoptotic cues.

Original languageEnglish
Pages (from-to)32-44
Number of pages13
JournalArchives of Biochemistry and Biophysics
Volume528
Issue number1
DOIs
StatePublished - Dec 1 2012

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Keywords

  • Allosteric regulation
  • Ligand binding
  • Membrane insertion
  • Molten globule
  • Protein oligomerization

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Bhat, V., Kurouski, D., Olenick, M. B., McDonald, C. B., Mikles, D. C., Deegan, B. J., Seldeen, K. L., Lednev, I. K., & Farooq, A. (2012). Acidic pH promotes oligomerization and membrane insertion of the BclXL apoptotic repressor. Archives of Biochemistry and Biophysics, 528(1), 32-44. https://doi.org/10.1016/j.abb.2012.08.009