![]() After synthesis, α2AP is enzymatically modified in the circulation at both the N- and C-terminus, which affects its fibrin-crosslinking and plasmin(ogen) binding capabilities respectively ( 18). Α2AP is primarily synthesized by hepatocytes in the liver and released into the blood ( 16, 17). A ~55 residue long C-terminus (red) (Asn 410-Lys 464 N 410-K 464) of α2AP is important for initial binding with plasmin due to the presence of multiple lysine residues. ![]() Plasmin cleaves at Arg 376-Met 377 bond (R 376-M 377, yellow highlighted, and red arrow) in the reactive center loop to form the inactive complex. The reactive center loop (magenta) protrudes out from the central serpin domain (green) of α2AP. Gln 14 (Q 14) residue of α2AP is cross-linked to fibrin by transglutaminase enzyme, activated factor XIII. The N-terminus (blue) of α2AP is cleaved in the circulation by APCE at the Pro 12-Asn 13 site (P 12-N 13, yellow highlighted and Red arrow) to form Asn 13-α2AP which represents 70% of blood α2AP levels. ![]() α2AP has a central serpin domain and, N- & C-terminal extensions with specific functions. The protein structure of human α2AP was generated by homology modeling using an online I-TASSER server ( 9) based on the crystal structure of mouse α2AP (PDB: 2R9Y) ( 10). However, mutations in the α2AP molecule or monoclonal antibodies against α2AP can change the plasmin-α2AP interaction to an enzyme-substrate reaction (an alternate mechanism of serpin interaction) where active plasmin leaves the complex after cleaving α2AP ( 15).įigure 1. Plasmin then cleaves the reactive center loop of α2AP at Arg 376-Met 377 bond and forms an inactive, covalent complex ( 1– 3, 14). Mechanistically, the C-terminal lysine residues of α2AP initially bind non-covalently to the kringle domains of plasmin to form a 1:1 stoichiometric complex ( 13). Structurally, α2AP is a unique serpin ( Figure 1) with a 12 amino acid N-terminus, a central serpin domain and a C-terminal tail that is ~55-residues long ( 10– 12). α2AP is present in the blood at nearly half the concentration (~1 μM) of its target enzyme precursor, plasminogen (~2 μM) ( 6, 8). ![]() α2AP was first described by three different investigators as the fast-acting inhibitor of plasmin ( 4– 6), who named it differently as α2-plasmin inhibitor ( 5), antiplasmin ( 6) and primary plasmin inhibitor ( 4, 7). Α2AP (also known as α2-plasmin inhibitor, antiplasmin, serpinf2, plasmin inhibitor), is an ultrafast covalent inhibitor of plasmin ( 1– 3) and, is a crucial member of the serine protease inhibitor (serpin) family. In this review, we will discuss the key role played by α2AP in controlling thrombosis and fibrinolysis and, we will consider its potential value as a therapeutic target in cardiovascular diseases and ischemic stroke.Īlpha2-Antiplasmin (α2AP) is the Serpin That Kills Plasmin Recent studies also show that α2AP is required for the development of stasis thrombosis by inhibiting the early activation of effective fibrinolysis. Through these mechanisms and others, α2AP contributes to brain injury, hemorrhage and swelling in experimental ischemic stroke. In addition, α2AP fosters the development of microvascular thrombosis and enhances matrix metalloproteinase-9 expression. Mechanistic studies in disease models indicate that α2AP stops the body's own fibrinolytic system from dissolving pathologic thrombi that cause venous thrombosis, pulmonary embolism, arterial thrombosis, and ischemic stroke. Epidemiology studies have shown an association between high α2AP levels and increased risk or poor outcome in cardiovascular diseases. However, studies of humans and mice with genetic deficiency of α2AP have expanded our understanding of this serpin, particularly in disease states.
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