Authors: (Aleksandra Topic—Institute of Medical Biochemistry, Faculty of Pharmacy, Belgrade, Serbia)
Abstract: Serpins play a critical role in maintaining homeostasis. Approximately two-thirds of human serpins perform extracellular roles, and the rest are localized and function intracellular. There are inhibitory and non-inhibitory serpins. In maintaining homeostasis, serpins are involved in a number of fundamental biological processes such as extracellular matrix remodeling, pro-hormone conversion, intracellular proteolysis, blood pressure, tumor suppression, hormone transport, viral/parasite pathogenicity, modulation of inflammatory response, cell differentiation, cell migration, protein folding, fibrinolysis, complement cascade and blood coagulation. Severe, human serpin-related diseases are emphysema, liver disease, massive thrombosis or bleeding, hereditary angioedema, dementia, angiopathy and tumor invasion. Inhibitory serpins are „suicide‟ or „single use‟ inhibitors that use a unique and extensive conformational change to inhibit proteinases. One hallmark of serpins is the reactive centre loop (RCL), a protein motif with a scissile bond, which is cleave by the target proteinase. The structure of the RCL is crucial for the ability of the protein to undergo a „stressed to relaxed‟ (S→R) conformational change. The active serpins are in metastable „stressed form‟, which is essential for their inhibition role. They can be present in various conformations: native inhibitory with an exposed RCL, latent with a partially inserted RCL or non-inhibitory due to complex formation, cleavage, oxidation of reactive centre residues or polymerization. Any mechanism which reduces the functional level of serpins such as oxidative inactivation, inactivation by non-target proteinases or genetic aberration (mutations), may lead to the pathological process. Serpins are especially vulnerable to mutations, which could alter their native conformations. Aberrations of conformation frequently occur and could lead to a range of diseases that are grouped together and named as the serpinopathies. Nowadays, well-established serpinopathies that reflect the functions and site of synthesis of the individual serpins are emphysema, cirrhosis, thrombosis and dementia. More than 200 different serpins mutations have been identified as the cause of various diseases. Mutations which cause inappropriate conformational change (or misfolding) results in two common outcomes. One is a promotion inappropriate transition to the monomeric latent state with reduction of active inhibitory serpin (antithrombin variants), and the other is serpin polymerization, when the RCL of one serpin molecule inserts into β-sheet A of another to form a dimer, which subsequently extends to form long chains of inactive polymers (alpha-1-antitrypsin variants).