Sandbox Reserved 596: Difference between revisions
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'''PZ''' | '''PZ''' | ||
Bovine PZ was first identified by Prowse and Esnouf in 1977 and human PZ, consisting of 360 amino acid residues and having a molecular weight of 62kDa, was first isolated and studied by Broze Jr. and Miletich in 1984. The gene coding for human PZ, PROZ, was found in 1998 on chromosome 13 at location 13q34 and is composed of a 389 bp promoter and nine exons (one being an alternative exon). [1,4] PZ is a single-chain glycoprotein with a 13 γ-carboxyglutamic (residues 7, 8, 11, 15, 17, 20, 21, 26, 27, 30, 33, 35 and 40) acid residues (Gla) N-terminal domain (residues 1-46), two epithelial growth factor (EGF)-like domains (EGF1 residues 47-830, EGF2 residues 85-126), and a C-terminal serine protease (SP)- like domain (residues 135-360) (Figure 1). | [[Image:PZ Structure 2.GIF]] | ||
Bovine PZ was first identified by Prowse and Esnouf in 1977 and human PZ, consisting of 360 amino acid residues and having a molecular weight of 62kDa, was first isolated and studied by Broze Jr. and Miletich in 1984. The gene coding for human PZ, PROZ, was found in 1998 on chromosome 13 at location 13q34 and is composed of a 389 bp promoter and nine exons (one being an alternative exon). [1,4] PZ is a single-chain glycoprotein with a 13 γ-carboxyglutamic (residues 7, 8, 11, 15, 17, 20, 21, 26, 27, 30, 33, 35 and 40) acid residues (Gla) N-terminal domain (residues 1-46), two epithelial growth factor (EGF)-like domains (EGF1 residues 47-830, EGF2 residues 85-126), and a C-terminal serine protease (SP)- like domain (residues 135-360) (Figure 1). | |||
PZ is very similar to the factor that it serves to inhibit, FXa. Both are vitamin k-dependent proteins with their EGF2 domain closely grouped with their SP domain. Although 33% homologous in sequence to serine protease factor Xa (FXa), PZ is not enzymatically active because it lacks the serine (Ser195) and histidine (His57) of the catalytic triad, giving its oxyanion hole and S1 pocket an inactive configuration. [5] PZ cannot perform the same interactions as FXa because PZ’s oxyanion hole does not have the same stabilizing interactions. PZ’s activation peptide is 5 residues shorter than FXa, and has a methionine (M312) at position 194 with its side chain pointing in the opposite direction of D194 in FXa. The S1 pocket of PZ is occupied by a glutamine (Q334) at position 216, a large tryptophan (W311) at 193 (G216 and G193 in FXa), and a half turn of 310 helix of residues 189-192 (residues 307-310 in PZ). [4] | PZ is very similar to the factor that it serves to inhibit, FXa. Both are vitamin k-dependent proteins with their EGF2 domain closely grouped with their SP domain. Although 33% homologous in sequence to serine protease factor Xa (FXa), PZ is not enzymatically active because it lacks the serine (Ser195) and histidine (His57) of the catalytic triad, giving its oxyanion hole and S1 pocket an inactive configuration. [5] PZ cannot perform the same interactions as FXa because PZ’s oxyanion hole does not have the same stabilizing interactions. PZ’s activation peptide is 5 residues shorter than FXa, and has a methionine (M312) at position 194 with its side chain pointing in the opposite direction of D194 in FXa. The S1 pocket of PZ is occupied by a glutamine (Q334) at position 216, a large tryptophan (W311) at 193 (G216 and G193 in FXa), and a half turn of 310 helix of residues 189-192 (residues 307-310 in PZ). [4] | ||
The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade by interacting with the serine protease thrombin 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 human 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 the serpin protein Z-dependent protease inhibitor (ZPI). The PZ binds to ZPI and then carries the serpin to associate with phospholipid membrane bound FXa (follows right side of Figure 2). [6] | The function of PZ was studied in 1991 by Hogg and Stenflo, who initially hypothesized PZ to amplify the coagulation cascade by interacting with the serine protease thrombin 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 human 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 the serpin protein Z-dependent protease inhibitor (ZPI). The PZ binds to ZPI and then carries the serpin to associate with phospholipid membrane bound FXa (follows right side of Figure 2). [6] | ||
[[Image:Figure_2.JPG]] | |||
