title: Structural analysis of protein Z gene variants in patients with foetal losses.
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.
authors.affiliation: Elvira Grandone, MD, PhD, Atherosclerosis and Thrombosis Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia, Italy, Tel./Fax: +39 0 882 416273, E-mail: e.grandone@operapadrepio.it.
authors.forename: R
authors.initials: R
authors.lastname: Caliandro
authors.forename: G
authors.initials: G
authors.lastname: Nico
authors.forename: G
authors.initials: G
authors.lastname: Tiscia
authors.forename: G
authors.initials: G
authors.lastname: Favuzzi
authors.forename: V
authors.initials: V
authors.lastname: De Stefano
authors.forename: E
authors.initials: E
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Margaglione
authors.forename: E
authors.initials: E
authors.lastname: Grandone
mesh_terms: D000022:Abortion, Spontaneous / Q000097:blood*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000378:metabolism; D001777:Blood Coagulation; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D001798:Blood Proteins; C026080:plasma protein Z