VWD domain stabilization by autocatalytic Asp-Pro cleavage.

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Von Willebrand factor type D (VWD) domains are prevalent in extracellular proteins.
• Many VWD domains contain a Gly-Asp-Pro-His (GDPH) motif cleaved post-translationally.
• Fc IgG binding protein (FCGBP) possesses 13 VWD domains, 11 with GDPH sites.

Purpose of the Study:

• To investigate the structural and biophysical effects of Asp-Pro cleavage in an FCGBP VWD domain.
• To understand how post-translational cleavage influences protein stability and structure.

Main Methods:

• X-ray crystallography to determine the structure of an FCGBP segment.
• Biophysical analysis to assess proteolytic degradation resistance.
• Comparative structural analysis of VWD domains.

Main Results:

• Endogenous Asp-Pro cleavage increases resistance to exogenous proteolysis.
• Crystal structure revealed tertiary interactions at new chain termini post-cleavage.
• The Gly-Asp peptide bond upstream of cleavage adopted a cis configuration.
• A global organizational difference was observed in the FCGBP VWD domain structure.

Conclusions:

• Asp-Pro cleavage in FCGBP VWD domains confers proteolytic resistance.
• Post-translational cleavage induces local and global structural changes.
• VWD domain plasticity, influenced by cleavage, may be crucial for extracellular functions.