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  • The majority of serpins inhibit serine proteases but serpins


    The majority of serpins inhibit serine proteases, but serpins that inhibit caspases or papain-like cysteine proteases have also been identified [4], [5]. Inhibitory serpins are ‘suicide’ or ‘single use’ inhibitors that use a unique conformational change to inhibit proteases. This conformational transition is termed the ‘stressed (S) to relaxed (R) transition’. Native serpins are in fact trapped in an metastable state, rather than their most stable conformation (they represent an exception to Anfinsen’s law) [6].
    Other functions of serpins Sometimes serpins perform a non-inhibitory function. Several human serpins function as molecular chaperones, hormone transporters, or tumor suppressors [7], [8]. They are involved in processes as diverse as dorsal-ventral axis formation, [Ala92]-p16 (84-103) condensation in chicken erythrocytes and immunoregulation in Drosophila. For instance Maspin, a member of clade B has a RSL (Reactive Site Loop) which is shorter than most RSL of the serpin superfamily and that is involved in cell migration [9]. Pigment Epithelial-Derived Factor (PEDF) is also a non inhibitory serpin with neuroprotective and antiangiogenic effects [8]. When nitrosylated, the alpha antitrypsin increases insulin-induced mitogenesis in various fibroblast and epithelial cell lines, and inhibits cell growth in human plasma [10], [11].
    Phylogenetic evolution The evolutionary origin of serpins is unclear although their distribution suggests that serpins may have arisen early in eukaryotic evolution [12]. The clade B consists of 13 members in humans. Their genes are located at two genomic loci: 6p25 (SERPINB1, -6 and -9) and 18q21 (SERPINB2, −3, −4, −5, −7, −8, −10, −11, −12 and −13). They display seven or eight exons. Two models exist to explain the presence of two clade B loci in humans. The first proposes duplication of the entire 6p25 locus followed by several single gene duplications at 18q21. The second proposes the opposite: the duplication of a single gene from 18q21 to 6p25, followed by successive duplications in this location [3].
    SERPINB1 SERPINB1 (that has different names depending on the species: human MNEI; mouse elastase inhibitor, horse and pig Leukocyte Elastase Inhibitor) is an inhibitor of neutrophil elastase present particularly in granulocytes and macrophages, although it [Ala92]-p16 (84-103) can be found at different concentrations in all tissues. SERPINB1 inhibits both elastase-like and chymotrypsin-like proteases through two distinct P1 (amino acid in the Nt direction of the cleaved bond) residues [13]. This serpin is in the group formerly called ov-serpin subfamily, which includes plasminogen activator inhibitor 2 and squamous cell carcinoma antigens 1 and 2 (SCCA1 and SCCA2) and maspin [3], [14]. SERPINB1 is an intracellular protein and acts primarily to protect the cell from proteases released into the cytoplasm during stress. This view is supported by KO mice which have a decreased viability of neutrophils [15]. This is consistent with its role as a protector of these cells from their own granular proteases. This function has been recently highlighted using myeloid conditional knock out and transgenic mice. In this paper Burgener et al. clearly show the correlation between neutrophil survival and the level of SERPINB1 (B1a in mice) [16]. Because of the lack of a cleavable hydrophobic signal sequence, SERPINB1 resides mainly in cytosol. It is also detectable in bronchoalveolar lavage fluid during lung inflammatory diseases. A lot of work has been performed investigating the impact of SERPINB1 on the control of extracellular neutrophil elastase released during chronic infections, particularly during respiratory diseases [17], [18]. SERPINB1 has also been described as a potent inhibitor of human granzyme H as well as elastase, cathepsin G and D, and proteinase-3 [19]. Other chymotrypsin-like proteases, such as chymase, and chymotrypsin, were also reported to interact with SERPINB1 [13].