TY - JOUR
T1 - Structural analysis of protein Z gene variants in patients with foetal losses
AU - Caliandro, Rocco
AU - Nico, Giovanni
AU - Tiscia, Giovanni
AU - Favuzzi, Giovanni
AU - De Stefano, Valerio
AU - Rossi, Elena
AU - Margaglione, Maurizio
AU - Grandone, Elvira
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Flexibility analysis
KW - Molecular dynamics
KW - Mutants
KW - Protein Z
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U2 - 10.1160/TH13-01-0005
DO - 10.1160/TH13-01-0005
M3 - Article
C2 - 23846529
AN - SCOPUS:84883247249
VL - 110
SP - 534
EP - 542
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
SN - 0340-6245
IS - 3
ER -