Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

Int J Mol Sci. 2020 Dec 13;21(24):9473. doi: 10.3390/ijms21249473.

Abstract

Interferon-β (IFN-β) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-β and S100P lowering IFN-β cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633-639). S100P is a member of large family of multifunctional Ca2+-binding proteins with cytokine-like activities. To probe selectivity of IFN-β-S100 interaction with respect to S100 proteins, we used surface plasmon resonance spectroscopy, chemical crosslinking, and crystal violet assay. Among the thirteen S100 proteins studied S100A1, S100A4, and S100A6 proteins exhibit strictly Ca2+-dependent binding to IFN-β with equilibrium dissociation constants, Kd, of 0.04-1.5 µM for their Ca2+-bound homodimeric forms. Calcium depletion abolishes the S100-IFN-β interactions. Monomerization of S100A1/A4/A6 decreases Kd values down to 0.11-1.0 nM. Interferon-α is unable of binding to the S100 proteins studied. S100A1/A4 proteins inhibit IFN-β-induced suppression of MCF-7 cells viability. The revealed direct influence of specific S100 proteins on IFN-β activity uncovers a novel regulatory role of particular S100 proteins, and opens up novel approaches to enhancement of therapeutic efficacy of IFN-β.

Keywords: S100 protein; cancer; cytokine; interferon; protein–protein interaction.

MeSH terms

  • Amino Acid Sequence
  • Calcium / chemistry
  • Calcium / metabolism*
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / metabolism
  • Cardiovascular Diseases / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Survival / drug effects
  • Dimerization
  • Humans
  • Interferon-beta / metabolism*
  • Kinetics
  • MCF-7 Cells
  • Models, Chemical
  • Molecular Docking Simulation
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Neoplasms / metabolism
  • Nervous System Diseases / metabolism
  • Protein Binding
  • Protein Conformation / drug effects
  • S100 Calcium Binding Protein A6 / chemistry
  • S100 Calcium Binding Protein A6 / metabolism
  • S100 Calcium-Binding Protein A4 / chemistry
  • S100 Calcium-Binding Protein A4 / metabolism
  • S100 Proteins / chemistry
  • S100 Proteins / metabolism*
  • Sequence Alignment
  • Surface Plasmon Resonance

Substances

  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Neoplasm Proteins
  • S100 Calcium Binding Protein A6
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100A1 protein
  • S100P protein, human
  • S100A6 protein, human
  • S100A4 protein, human
  • Interferon-beta
  • Calcium