Ligand binding and membrane insertion compete with oligomerization of the BclXL apoptotic repressor

Vikas Bhat, Caleb B. McDonald, David C. Mikles, Brian J. Deegan, Kenneth L. Seldeen, Margaret L. Bates, Amjad Farooq

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

B-cell lymphoma extra large (BclXL) apoptotic repressor plays a central role in determining the fate of cells to live or die during physiological processes such as embryonic development and tissue homeostasis. Herein, using a myriad of biophysical techniques, we provide evidence that ligand binding and membrane insertion compete with oligomerization of BclXL in solution. Of particular importance is the observation that such oligomerization is driven by the intermolecular binding of its C-terminal transmembrane (TM) domain to the canonical hydrophobic groove in a domain-swapped trans fashion, whereby the TM domain of one monomer occupies the canonical hydrophobic groove within the other monomer and vice versa. Binding of BH3 ligands to the canonical hydrophobic groove displaces the TM domain in a competitive manner, allowing BclXL to dissociate into monomers upon hetero-association. Remarkably, spontaneous insertion of BclXL into DMPC/DHPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine/ 1,2-dihexanoyl-sn-glycero-3-phosphocholine) bicelles results in a dramatic conformational change such that it can no longer recognize the BH3 ligands in what has come to be known as the "hit-and-run" mechanism. Collectively, our data suggest that oligomerization of a key apoptotic repressor serves as an allosteric switch that fine-tunes its ligand binding and membrane insertion pertinent to the regulation of apoptotic machinery.

Original languageEnglish (US)
Pages (from-to)57-77
Number of pages21
JournalJournal of molecular biology
Volume416
Issue number1
DOIs
StatePublished - Feb 10 2012

Keywords

  • allosteric regulation
  • BclXL apoptotic repressor
  • ligand binding
  • membrane insertion
  • protein oligomerization

ASJC Scopus subject areas

  • Molecular Biology

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