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The pro-apoptotic domain of BIM protein forms toxic amyloid fibrils

Ravit Malishev1, Shani Ben-Zichri1, Ofek Oren2

  • 1Department of Chemistry and Ilse, Katz Institute for Nanotechnology, Ben Gurion University of the Negev, 84105, Beer Sheva, Israel.

Cellular and Molecular Life Sciences : CMLS
|August 27, 2020
PubMed

Insights

The core apoptotic domain of BIM (BIM-BH3 motif) forms toxic amyloid fibrils, revealing a new mechanism for cell death in diseases. This finding highlights the amyloidogenic potential of apoptotic peptides.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Neuroscience

Background:

  • BIM is a crucial protein regulating apoptosis (programmed cell death).
  • Protein misfolding diseases, like Alzheimer's disease, involve significant neuronal cell death.
  • BIM's role in this neuronal cell death has been hypothesized but not fully elucidated.

Purpose of the Study:

  • To investigate the structural properties of the BIM-BH3 motif, the core pro-apoptotic domain of BIM.
  • To determine if the BIM-BH3 motif can form amyloid fibrils and assess their cellular effects.
  • To explore the potential link between BIM-BH3 amyloid formation and neuronal cell death in protein misfolding diseases.

Main Methods:

  • Synthesized the BIM-BH3 motif peptide and a longer variant.
  • Utilized biophysical techniques to characterize amyloid fibril formation.
  • Assessed the cytotoxicity and mitochondrial effects of the BIM-BH3 fibrils using cell-based assays.
  • Examined the impact of fibrils on mitochondrial membrane mimics.

Main Results:

  • The BIM-BH3 motif spontaneously formed amyloid fibrils.
  • These BIM-BH3 fibrils demonstrated significant cytotoxicity.
  • The fibrils disrupted mitochondrial functions and altered mitochondrial membrane structures.
  • A slightly longer BIM-derived peptide did not form fibrils or exhibit cytotoxicity.

Conclusions:

  • The BIM-BH3 motif possesses intrinsic amyloidogenic properties.
  • Formation of BIM-BH3 amyloid fibrils represents a novel mechanism of apoptosis.
  • This finding provides new insights into the pathogenesis of neurodegenerative diseases involving protein misfolding and neuronal death.
Keywords:
ApoptosisBIMBcl-2 proteinsBeta-amyloidFibrilsMitochondria

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