1. Academic Validation
  2. Site-Dependent Cysteine Lipidation Potentiates the Activation of Proapoptotic BAX

Site-Dependent Cysteine Lipidation Potentiates the Activation of Proapoptotic BAX

  • Cell Rep. 2020 Mar 10;30(10):3229-3239.e6. doi: 10.1016/j.celrep.2020.02.057.
Daniel T Cohen 1 Thomas E Wales 2 Matthew W McHenry 3 John R Engen 2 Loren D Walensky 4
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
  • 2 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: loren_walensky@dfci.harvard.edu.
Abstract

Bcl-2 Family proteins converge at the mitochondrial outer membrane to regulate Apoptosis and maintain the critical balance between cellular life and death. This physiologic process is essential to organism homeostasis and relies on protein-protein and protein-lipid interactions among Bcl-2 Family proteins in the mitochondrial lipid environment. Here, we find that trans-2-hexadecenal (t-2-hex), previously implicated in regulating BAX-mediated Apoptosis, does so by direct covalent reaction with C126, which is located on the surface of Bax at the junction of its α5/α6 core hydrophobic hairpin. The application of nuclear magnetic resonance spectroscopy, hydrogen-deuterium exchange mass spectrometry, specialized t-2-hex-containing liposomes, and Bax mutational studies in mitochondria and cells reveals structure-function insights into the mechanism by which covalent lipidation at the mitochondria sensitizes direct Bax activation. The functional role of Bax lipidation as a control point of mitochondrial Apoptosis could provide a therapeutic strategy for Bax modulation by chemical modification of C126.

Keywords

BAX; BCL-2 family; apoptosis; cysteine lipidation; lipid-derived electrophile; membrane permeabilization; mitochondria; post-translational modification; sphingolipid metabolism.

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