Serpin Inhibition Mechanism: A Delicate Balance between Native Metastable State and Polymerization

The serpins (serine proteinase inhibitors) are structurally similar but functionally diverse proteins that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. Serpins play absolutely critical role in the control of proteases involved in the inflammatory, complement, coagulation and fibrinolytic pathways and are associated with many conformational diseases. Serpin's native state is a metastable state which transforms to a more stable state during its inhibitory mechanism. Serpin in the native form is in the stressed (S) conformation that undergoes a transition to a relaxed (R) conformation for the protease inhibition. During this transition the region called as reactive center loop which interacts with target proteases, inserts itself into the center of β-sheet A to form an extra strand. Serpin is delicately balanced to perform its function with many critical residues involved in maintaining metastability. However due to its typical mechanism of inhibition, naturally occurring serpin variants produces conformational instability that allows insertion of RCL of one molecule into the β-sheet A of another to form a loop-sheet linkage leading to its polymerization and aggregation. Thus understanding the molecular basis and amino acid involved in serpin polymerization mechanism is critical to devising strategies for its cure. 1. Introduction Serpins (serine proteinase inhibitors) are the largest super family of protease inhibitors involved in many critical biological processes like blood coagulation, fibrinolysis, programmed cell death, development and inflammation [1–3]. Serpins are structurally heterogeneous and functionally diverse proteins found in the organisms ranging from viruses to vertebrates [4–6]. Over 400 different serpins have been identified in organisms including viruses, plants, insects, animals and prokaryotes [7]. Serpins like α-antitrypsin, α-antichymotrypsin, C1-inhibitors, antithrombin, and plasminogen activator inhibitor-1 (PAI), play absolutely critical role in the control of proteases involved in the inflammatory, complement, coagulation and fibrinolytic pathways, respectively, and are associated with diseases like emphysema/cirrhosis, angioedema, familial dementia, chronic obstructive bronchitis and thrombosis [8]. Not all serpins act as proteinase inhibitors some are inhibitors of other types of proteinases, while others are noninhibitors. For example, the viral serpin crmA inhibits interleukin-1 converting enzyme and squamous cell carcinoma, antigen-1 (SCCA-1) inhibits cysteinyl