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Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit

Fiona Aguilar1, Stacey Yu2, Robert A Grant1

  • 1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Structure (London, England : 1993)
|January 27, 2023
PubMed

Insights

Researchers identified new peptides that activate BAK, a key protein in apoptosis and cell death. These findings expand our understanding of BAK regulation and may lead to new cancer therapeutics.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Apoptosis is crucial for development and tissue homeostasis.
  • Dysregulation of apoptosis is linked to diseases like cancer.
  • BAK is an effector protein in apoptosis, activated by specific peptides.

Purpose of the Study:

  • To discover novel peptides that regulate the apoptotic effector BAK.
  • To explore the sequence space of peptides that can modulate BAK function.

Main Methods:

  • Computational protein design
  • Yeast surface display screening
  • Structure-based energy scoring
  • Liposome assays
  • Cytochrome c release assays
  • Crystal structure analysis

Main Results:

  • Identified 10 new BAK-binding peptides from human proteins (BNIP5, PXT1) and non-native sources.
  • Demonstrated that these peptides activate BAK, induce outer mitochondrial membrane permeabilization, and release cytochrome c.
  • Structural and binding studies showed similarities between BAK activators and inhibitors, suggesting complex regulation.

Conclusions:

  • A vast peptide sequence space can regulate BAK function.
  • The identified peptides provide new tools for studying apoptosis.
  • Findings may guide the development of novel therapeutics targeting BAK for diseases like cancer.
Keywords:
BAK activationBAK inhibitorBH3 peptidesBH3 profilingapoptosisbinding kineticspeptide design

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