Summary
The role of protein Z (PZ) in the etiology of human disorders is unclear. A number
of PZ gene variants, sporadic or polymorphic and found exclusively in the serine protease
domain, have been observed. Crystal structures of PZ in complex with the PZ-dependent
inhibitor (PZI) have been recently obtained. The aim of this study was a structural
investigation of the serine protease PZ domain, aiming at finding common traits across
disease-linked mutations. We performed 10–20 ns molecular dynamics for each of the
observed PZ mutants to investigate their structure in aqueous solution. Simulation
data were processed by novel tools to analyse the residue-by-residue backbone flexibility.
Results showed that sporadic mutations are associated with anomalous flexibility of
residues belonging to specific regions. Among them, the most important is a loop region
which is in contact with the longest helix of PZI. Other regions have been identified,
which hold anomalous flexibility associated with potentially protective gene variants.
In conclusion, a possible interpretation of effects associated with observed gene
variants is provided. The exploration of PZ/PZI interactions seems essential in explaining
these effects.
Keywords
Protein Z - mutants - molecular dynamics - flexibility analysis