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Interaction of Amphipathic Peptide from Influenza Virus M1 Protein with Mitochondrial Cytochrome Oxidase

Ilya P Oleynikov1, Roman V Sudakov1, Victor A Radyukhin1

  • 1A. N. Belozersky Institute of Physico-Chemical Biology, M. V. Lomonosov Moscow State University, Leninskie Gory 1, Bld. 40, Moscow 119992, Russia.

International Journal of Molecular Sciences
|February 25, 2023
PubMed

Insights

The peptide P4 inhibits cytochrome c oxidase (CcO) by binding to its Bile Acid Binding Site (BABS). This interaction disrupts the enzyme

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzyme Kinetics

Background:

  • Cytochrome c oxidase (CcO) possesses a Bile Acid Binding Site (BABS) that interacts with various amphipathic molecules.
  • Understanding the specific residues within BABS critical for ligand interaction is essential for elucidating CcO function.

Purpose of the Study:

  • To identify BABS-lining residues crucial for ligand interaction using peptide P4 and its derivatives.
  • To investigate the inhibitory mechanism of peptide P4 on CcO activity in solution and membrane environments.

Main Methods:

  • Utilized peptide P4 and derivatives (A1-A4) derived from M1 protein of influenza virus.
  • Assessed CcO activity in solution and membranes; analyzed peptide secondary structure via molecular dynamics and circular dichroism.
  • Investigated peptide-induced membrane pore formation and competitive inhibition kinetics.

Main Results:

  • Peptide P4 suppressed solubilized CcO oxidase activity (true Ki = 3 μM) but not peroxidase activity, indicating competition with dodecyl-maltoside and deoxycholate.
  • Derivatives A1 and A4 showed moderate inhibition (Ki(app)~20 μM), while A2 and A3 had minimal effect.
  • Mitochondrial membrane-bound CcO remained sensitive to P4 and A4 but became resistant to A1, potentially due to altered peptide secondary structure.

Conclusions:

  • Peptide P4 inhibits CcO by binding to BABS and potentially disrupting the proton channel K, with a critical role for a Trp residue.
  • The differential inhibition of membrane-bound vs. solubilized CcO suggests that peptide secondary structure and membrane environment influence inhibitory efficacy.
Keywords:
Bile Acids Binding Siteamphipathic ligandscell penetrating peptidescytochrome oxidaseregulationsecondary structureα-helix

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