{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSERPINA10, which encodes protein Z–dependent protease inhibitor (ZPI), is a plasma serpin that plays a critical anticoagulant role by inhibiting membrane‐associated coagulation proteases, most notably factor Xa and factor XIa. In the presence of its cofactor protein Z (PZ), ZPI rapidly forms a Michaelis complex on procoagulant membranes, an interaction that is further facilitated by calcium ions and negatively charged phospholipids. In addition, heparin can act as a template cofactor to accelerate the inhibition, although recent studies indicate that heparin binding to ZPI may induce conformational changes that antagonize PZ interaction. Structural analyses reveal that ZPI utilizes a unique reactive center featuring a tyrosine residue—which contrasts with the typical arginine in other serpins—to confine its inhibitory activity exclusively to sites where cofactors and membrane surfaces overcome its intrinsic kinetic limitations. Oxidative modifications of phospholipid vesicles have also been shown to impair ZPI’s activity, potentially shifting the balance toward a prothrombotic state."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, the specificity and efficiency of ZPI in targeting coagulation proteases depend on precise protein–protein interactions. Detailed kinetic and mutational studies have shown that recognition of factor Xa and related proteases involves critical contacts between the reactive center loop of ZPI and complementary autolysis and heparin-binding regions on the proteases. Structural modeling, including comparisons with antithrombin, emphasizes that ZPI’s unusual P1 tyrosine residue is central to its selective inhibition, which is further regulated by distinct binding determinants that modulate its complex formation with PZ. Innovative approaches employing site‐specific fluorophore labeling have further clarified the thermodynamic and multistep binding mechanisms underlying ZPI’s catalytic activation by PZ."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}, {"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, both quantitative alterations and genetic variations in SERPINA10 have been linked to disorders of coagulation. Several studies report that rare nonsense and missense mutations in the ZPI gene may increase the risk of venous thrombosis, recurrent miscarriage, and other prothrombotic conditions, although associations are sometimes inconsistent across populations. In addition, aberrant expression and tissue distribution of ZPI—and its interaction with protein Z—have been observed in various pathological settings, including colon, lung, and gastric cancers as well as in conditions such as haemophilia and preeclampsia. Such findings collectively suggest that dysregulation of ZPI may disrupt the fine balance of thrombin generation and fibrin formation, thereby contributing to both bleeding and thrombotic phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xin Huang, Richard Swanson, George J Broze, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Basis for the specificity and activation of the serpin protein Z-dependent proteinase inhibitor (ZPI) as an inhibitor of membrane-associated factor Xa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.112748"}], "href": "https://doi.org/10.1074/jbc.M110.112748"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20427285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20427285"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xin Huang, Alireza R Rezaie, George J Broze, et al. 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