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From Proteopedia

Protein Z

Table of Contents

Background

Protein Z (PZ) is a vitamin k-dependent glycoprotein made in the liver and involved in the blood-clot-forming coagulation cascade. Bovine PZ was first identified by Prowse and Esnouf in 1977 and Human PZ was first isolated and studied by Broze Jr. and Miletich in 1984. The gene coding for PZ, called PROZ, was found in 1998 on chromosome 13 at location 13q34 and is composed of nine exons (one being an alternative exon).

Structure

PZ is a single-chain protein with a N-terminal domain rich in γ-carboxyglutamic acids (Gla), two epidermal growth factor-like (EGF) domains and a C-terminal serine protease-like domain and has a molecular weight of 62 kDa. PZ genetically and structurally mimics other factors of the coagulation cascade but it is not a catalyticaly active enzyme. PZ is not like the other vitamin k-dependent coagulation factors because it does not have an active center, thus it lacks the Ser and His of the catalytic triad needed for the active site of serine proteases, like the coagulation factors VII, IX, X, and protein C. PZ's 390 amino acid sequence is N-terminally analogous to the serine protease coagulation factors, whose similarly composed genes are found clustered together along with PROZ on chromosome 13.

Function

The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade but found that bovine PZ has a higher affinity for thrombin than human PZ due to a 36 amino acid addition to the bovine PZ's C-terminus. Furthermore, they found that PZ virtually had no involvement in binding thrombin to phospholipids. It was not until 1998 that Han et al. described PZ present in the body as a complex with protein Z-dependent protease inhibitor (ZPI). The ZPI and PZ complex acts as an inhibitor of factor Xa (FXa), an important enzyme in prothrombin activation, attached to platelets and other phopholipid surfaces (forming a calcium-dependent teritary complex). It has been shown that PZ and ZPI travel the body in plasma already bonded together as a complex and later binds to activated FXa bound to the phospholipid membrane. PZ has a high affinity for ZPI and speeds up its interaction FXa by 1000x with calcium and phospholipids present. While ZPI requires the presence of PZ, calcium, and phospholipids to inhibit FXa, ZPI does not need other components to inhibit another coagulation factor, factor XI.

Clinical Relevance

References