Structural analysis of protein Z gene variants in patients with foetal losses

Valerio De Stefano, Elena Rossi, Rocco Caliandro, Giovanni Nico, Giovanni Tiscia, Giovanni Favuzzi, Maurizio Margaglione, Elvira Grandone

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)534-542
Number of pages9
JournalThrombosis and Haemostasis
Volume110
DOIs
Publication statusPublished - 2013

Keywords

  • FETAL LOSS
  • PROTEIN Z

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