title: Unique secretion mode of human protein Z: its Gla domain is responsible for inefficient, vitamin K-dependent and warfarin-sensitive secretion.
abstract: Protein Z is a vitamin K-dependent plasma glycoprotein that is involved in the regulation of blood coagulation. Plasma concentrations of protein Z vary widely between subjects and are greatly reduced during warfarin therapy. We developed a sensitive and quantitative assay for protein secretion using a secretory luciferase to explore the mode of secretion of protein Z compared with that of factor X. Protein Z secretion was much less efficient than factor X and was totally dependent upon added vitamin K, while factor X secretion was not. Protein Z secretion was highly sensitive to warfarin treatment of the synthesizing cells. In contrast, although factor X secretion was not precluded by warfarin, its gamma-carboxylation was completely blocked. An exchange of the propeptide and/or gamma-carboxyglutamic acid domain between protein Z and factor X reproduced the inefficient and warfarin-sensitive secretion pattern of protein Z, and vice versa. Joining of the propeptide and gamma-carboxyglutamic acid domain to luciferase also demonstrated that the gamma-carboxyglutamic acid domain of protein Z was responsible for its warfarin-sensitive secretion. Thus, it was concluded that the difference observed in secretion patterns of protein Z and factor X was mainly based on the structure of their gamma-carboxyglutamic acid domains.
authors.affiliation: Department of Molecular Patho-Biochemistry and Patho-Biology of Blood Circulation, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Souri
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwata
authors.forename: Wei Guang
authors.initials: WG
authors.lastname: Zhang
authors.forename: Akitada
authors.initials: A
authors.lastname: Ichinose
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology*; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005170:Factor X / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary / Q000502:physiology; D014812:Vitamin K / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D001798:Blood Proteins; C026080:plasma protein Z; D014812:Vitamin K; D014859:Warfarin; D005170:Factor X