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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Mitochondria, chloroplasts, and gram-negative bacteria have transmembrane, beta-barrel proteins called porins to mediate the free diffusion of ions and metabolites across the membrane. Mitochondrial porin precursors contain conserved amino acid sequences called beta signals at their C-terminal. Beta signals have a  motif of PoXGXXHyXHy (Po-Polar, X-Any amino acid, G-Glycine, Hy-LargeHydrophobic), which are crucial for precursor recognition to initiate precursor assembly. Beta-barrel...
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In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
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Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
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BAX mitochondrial integration is regulated allosterically by its α1-α2 loop.

Michael A Dengler1,2,3, Leonie Gibson1, Jerry M Adams4,5

  • 1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC, 3052, Australia.

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The BAX α1-α2 loop regulates apoptosis by controlling mitochondrial outer membrane integration. Mutations in the N-terminal half impair this process, potentially promoting tumor survival.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • BAX protein activation is a critical step in apoptosis, involving conformational changes from a cytosolic monomer to homo-oligomers.
  • These oligomers permeabilize the mitochondrial outer membrane (MOM), initiating programmed cell death.
  • The BAX α1-α2 loop's role in this activation process remains incompletely understood.

Purpose of the Study:

  • To investigate the functional significance of the BAX α1-α2 loop in BAX-mediated apoptosis.
  • To determine how specific mutations within the α1-α2 loop affect BAX conformational changes and MOM integration.
  • To explore the implications of α1-α2 loop mutations in cancer.

Main Methods:

  • Utilized three mutagenic approaches: loop region replacement, alanine scanning, and analysis of naturally occurring tumor mutations.
  • Assessed the responsiveness of BAX variants to death signals like tBID.
  • Evaluated the impact of mutations on MOM integration and BAX stability.

Main Results:

  • Mutations in the N-terminal half of the α1-α2 loop reduced responsiveness to death signals and impaired MOM integration by allosterically affecting the α9 transmembrane anchor.
  • N-terminal loop variants, found enriched in tumors, were shown to hinder MOM integration.
  • Most C-terminal loop variants decreased BAX stability, with some variants exhibiting enhanced apoptotic function.

Conclusions:

  • The N-terminal and C-terminal halves of the BAX α1-α2 loop possess distinct functions in apoptosis regulation.
  • The N-terminal half acts as an allosteric regulator of BAX activation, controlling MOM integration post-death signal.
  • Enrichment of N-terminal loop mutations in tumors suggests a role in tumor cell survival and highlights the loop as a therapeutic target.