Foldon unfolding mediates the interconversion between M(pro)-C monomer and 3D domain-swapped dimer

Area of Science:

• Biochemistry
• Structural Biology
• Virology

Background:

• The C-terminal domain of SARS-CoV main protease (M(pro)-C) exists in monomeric and 3D domain-swapped dimeric forms.
• Understanding the interconversion mechanism is crucial for protease function and antiviral strategies.

Purpose of the Study:

• To investigate the mechanism of reversible topological interconversion of M(pro)-C between monomeric and 3D domain-swapped dimeric states.
• To elucidate the role of protein folding and hydrophobic interactions in this process.

Main Methods:

• The study likely involved techniques such as X-ray crystallography, NMR spectroscopy, and biophysical assays to characterize protein structure and dynamics.
• Analysis of protein folding transitions and self-association properties.

Main Results:

• M(pro)-C reversibly interconverts between monomer and 3D domain-swapped dimer topologies under physiological conditions.
• The interconversion proceeds without exposing the protein's hydrophobic core to solvent.
• A key step involves the order-to-disorder transition of the C-terminal α(5)-helix foldon, which facilitates monomer self-association and domain swapping.

Conclusions:

• A novel mechanism for 3D domain swapping is proposed, involving a transient dimeric intermediate that allows core unpacking and helix swapping in a hydrophobic environment.
• This mechanism minimizes the energy required for the domain-swapping process, offering insights into protein dynamics and regulation.