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

Abstract

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.

SERPINB3 and B4: From biochemistry to biology

“…As a result, the protease gets translocated by over 70Å and its active site gets distorted. Distortion of the active site prevents the final hydrolysis events and results an irreversible covalent serpin-protease complex [22-26]. Like other SERPINs, SERPINB3 and B4 are believed to form a SDS-resistant complex via an acyl-oxyester bond with their proteases to inhibit their activities [16, 17, 19, 20].…”

Influence of hyperinsulinemic – hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von Willebrand factor in patients with type I diabetes

“…АТ-III -основной ингибитор тромбина, активиро-ванных IX, X и XII факторов, плазмина [25,33], активность которых повышается у больных СД1 [24,34]. Исходно на фоне гипергликемии концентрация АТ-III была значи-тельно выше нормативных значений, затем достоверно снижалась при достижении нормогликемии и сохраня-лась на этом уровне при переходе к гипогликемии (оста-ваясь достоверно выше верхней границы нормы).…”

Siropins, novel serine protease inhibitors from gut microbiota acting on human proteases involved in inflammatory bowel diseases

“…Moreover, serpins also operate through non inhibitory mechanisms on many physiological functions such as tumor suppression, molecular chaperone activity, chromatin compaction and hormone transport [1]. Unlike small protease inhibitors acting by a reversible way, serpins are distinguishable by their irreversible suicide mechanism of inhibition [7]. Indeed, the serpin inhibition activity is associated to the Reactive Center Loop (RCL) which interacts with target protease thereby resulting in the cleavage of the RCL that enables the establishment of a covalent acyl-enzyme complex.…”