Heparin activates PKR by inducing dimerization.

Area of Science:

• Biochemistry
• Immunology
• Molecular Biology

Background:

• Protein kinase R (PKR) is an interferon-induced kinase crucial for innate immunity.
• PKR activation, typically by double-stranded RNA, leads to protein synthesis inhibition via eIF2α phosphorylation.
• PKR is also activated by heparin, a sulfated glycosaminoglycan.

Purpose of the Study:

• To elucidate the mechanism of PKR activation by heparin using biophysical methods.
• To investigate the structural and thermodynamic basis of heparin-PKR interaction.
• To assess the potential of small molecules like heparin as activators of PKR for therapeutic purposes.

Main Methods:

• Biophysical techniques were employed to study PKR activation.
• Analytical ultracentrifugation was used to measure heparin-PKR binding and dimerization.
• Biochemical assays assessed PKR autophosphorylation upon heparin binding.

Main Results:

• Heparin, even as short as a hexasaccharide, binds strongly to PKR and induces autophosphorylation.
• Unlike dsRNA, heparin binds to the kinase domain of PKR.
• Analytical ultracentrifugation data support a model where heparin binding allosterically promotes PKR dimerization and activation.

Conclusions:

• PKR can be activated by heparin through binding to its kinase domain, leading to allosteric enhancement of dimerization.
• These findings reveal a novel mechanism of PKR activation by small molecules.
• Activated PKR represents a promising target for developing new antiviral therapies.