Molecular determinants of the binding specificity of BH3 ligands to BclXL apoptotic repressor

Vikas Bhat, Max B. Olenick, Brett J. Schuchardt, David C. Mikles, Caleb B. McDonald, Amjad Farooq

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

B-cell lymphoma extra-large protein (BclXL) serves as an apoptotic repressor by virtue of its ability to recognize and bind to BH3 domains found within a diverse array of proapoptotic regulators. Herein, we investigate the molecular basis of the specificity of the binding of proapoptotic BH3 ligands to BclXL. Our data reveal that while the BH3 ligands harboring the LXXX[A/S]D and [R/Q]XLXXXGD motif bind to BclXL with high affinity in the submicromolar range, those with the LXXXGD motif afford weak interactions. This suggests that the presence of a glycine at the fourth position (G+4) - relative to the N-terminal leucine (L0) within the LXXXGD motif - mitigates binding, unless the LXXXGD motif also contains arginine/glutamine at the -2 position. Of particular note is the observation that the residues at the +4 and -2 positions within the LXXX[A/S]D and [R/Q]XLXXXGD motifs appear to be energetically coupled - replacement of either [A/S]+4 or [R/Q]-2 with other residues has little bearing on the binding affinity of BH3 ligands harboring one of these motifs. Collectively, our study lends new molecular insights into understanding the binding specificity of BH3 ligands to BclXL with important consequences on the design of novel anticancer drugs.

Original languageEnglish (US)
Pages (from-to)573-582
Number of pages10
JournalBiopolymers
Volume101
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • BclXL-BH3 recognition
  • binding specificity
  • energetic coupling
  • salt dependence

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry

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