Heat-induced fibrillation of BclXL apoptotic repressor

Vikas Bhat, Max B. Olenick, Brett J. Schuchardt, David C. Mikles, Brian J. Deegan, Caleb B. McDonald, Kenneth L. Seldeen, Dmitry Kurouski, Mohd Hafeez Faridi, Mohammed M. Shareef, Vineet Gupta, Igor K. Lednev, Amjad Farooq

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The BclXL apoptotic repressor bears the propensity to associate into megadalton oligomers in solution, particularly under acidic pH. Herein, using various biophysical methods, we analyze the effect of temperature on the oligomerization of BclXL. Our data show that BclXL undergoes irreversible aggregation and assembles into highly-ordered rope-like homogeneous fibrils with length in the order of mm and a diameter in the μm-range under elevated temperatures. Remarkably, the formation of such fibrils correlates with the decay of a largely α-helical fold into a predominantly β-sheet architecture of BclXL in a manner akin to the formation of amyloid fibrils. Further interrogation reveals thatwhile BclXL fibrils formed under elevated temperatures show no observable affinity toward BH3 ligands, they appear to be optimally primed for insertion into cardiolipin bicelles. This salient observation strongly argues that BclXL fibrils likely represent an on-pathway intermediate for insertion into mitochondrial outer membrane during the onset of apoptosis. Collectively, our study sheds light on the propensity of BclXL to form amyloid-like fibrils with important consequences on its mechanism of action in gauging the apoptotic fate of cells in health and disease.

Original languageEnglish (US)
Pages (from-to)12-25
Number of pages14
JournalBiophysical Chemistry
Volume179
DOIs
StatePublished - Jan 1 2013

Keywords

  • Amyloid fibrils
  • Irreversible aggregation
  • Kinetic trap
  • Membrane insertion
  • α-β structural transition

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Organic Chemistry

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    Bhat, V., Olenick, M. B., Schuchardt, B. J., Mikles, D. C., Deegan, B. J., McDonald, C. B., Seldeen, K. L., Kurouski, D., Faridi, M. H., Shareef, M. M., Gupta, V., Lednev, I. K., & Farooq, A. (2013). Heat-induced fibrillation of BclXL apoptotic repressor. Biophysical Chemistry, 179, 12-25. https://doi.org/10.1016/j.bpc.2013.04.002