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<p>Mitochondria maintain a distinct biochemical environment that cooperates with pro-apoptotic BAX and BH3‑only proteins (e.g., BIM) to promote mitochondrial outer membrane permeabilization (MOMP), the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-<i>trans</i>-hexadecenal (2t‑hexadecenal) is a bioactive lipid that supports BAX-dependent MOMP. Using integrated structural and computational approaches, we determine that 2t‑hexadecenal binds within a distinct, dynamic region—a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8—we now term the “BAX actuating funnel” (BAF). Complementary biochemical and biophysical techniques reveal that 2t-hexadecenal non-covalently interacts with the BAF and cooperates with BIM to stimulate intramolecular activation of monomeric BAX prior to membrane association. BAX α8 mobility and proline 168-mediated allostery are critical determinants for 2t-hexadecenal synergy with BAX and BIM, as is alkenal length to stimulate BAF function. Collectively, this work imparts detailed molecular insights into how pro-apoptotic BCL-2 proteins and bioactive lipids non-covalently cooperate to initiate the mitochondrial pathway of apoptosis with implications for biological and therapeutic regulation.</p>

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A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Jesse D. Gelles,
  • Yiyang Chen,
  • Mark P. A. Luna-Vargas,
  • Ariele Viacava Follis,
  • Md Abdullah Al Noman,
  • Md Kabir,
  • Stella G. Bayiokos,
  • Jarvier N. Mohammed,
  • Tara M. Sebastian,
  • Ngoc Dung Pham,
  • Yi Shi,
  • Jian Jin,
  • Richard W. Kriwacki,
  • Jerry Edward Chipuk

摘要

Mitochondria maintain a distinct biochemical environment that cooperates with pro-apoptotic BAX and BH3‑only proteins (e.g., BIM) to promote mitochondrial outer membrane permeabilization (MOMP), the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t‑hexadecenal) is a bioactive lipid that supports BAX-dependent MOMP. Using integrated structural and computational approaches, we determine that 2t‑hexadecenal binds within a distinct, dynamic region—a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8—we now term the “BAX actuating funnel” (BAF). Complementary biochemical and biophysical techniques reveal that 2t-hexadecenal non-covalently interacts with the BAF and cooperates with BIM to stimulate intramolecular activation of monomeric BAX prior to membrane association. BAX α8 mobility and proline 168-mediated allostery are critical determinants for 2t-hexadecenal synergy with BAX and BIM, as is alkenal length to stimulate BAF function. Collectively, this work imparts detailed molecular insights into how pro-apoptotic BCL-2 proteins and bioactive lipids non-covalently cooperate to initiate the mitochondrial pathway of apoptosis with implications for biological and therapeutic regulation.