Serpins: Structure, function and molecular evolution

ArticleinThe International Journal of Biochemistry & Cell Biology 35(11):1536-47 · December 2003with20 Reads
DOI: 10.1016/S1357-2725(03)00134-1 · Source: PubMed
The superfamily of serine proteinase inhibitors (serpins) are involved in a number of fundamental biological processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and tumor suppression and are expressed in a cell-specific manner. The average protein size of a serpin family member is 350-400 amino acids, but gene structure varies in terms of number and size of exons and introns. Previous studies of all known serpins identified 16 clades and 10 orphan sequences. Vertebrate serpins can be conveniently classified into six sub-groups. We provide additional data that updates the phylogenetic analysis in the context of structural and functional properties of the proteins. From these, we can conclude that the functional classification of serpins relies on their protein structure and not on sequence similarity.
    • "Serine protease inhibitors (SPIs) have been identified in a variety of organisms in nature, being present in not only the bodies of various animals but also the secretions of parasites, hematophagous invertebrates, amphibian skins, and the venom glands of poisonous animals [1][2][3][4]. Protease inhibitors are capable of inhibiting the catalytic activity of proteolytic enzymes and are extensively distributed in all kingdoms of cellular life [5][6], signifying the importance of inhibiting proteolysis in their biological processes for survival. Among peptide protease inhibitors, the Kunitz-type protease inhibitors are a well-characterized subfamily, because of their abundance in several organisms, which usually consist of about 60 amino acid residues possessing three disulfide bridges and can strongly inhibit trypsin and chymotrypsin [7] . "
    [Show abstract] [Hide abstract] ABSTRACT: It is hypothesized that protease inhibitors play an essential role in survival of venomous animals through protecting peptide/protein toxins from degradation by proteases in their prey or predators. However, the biological function of protease inhibitors in scorpion venoms remains unknown. In the present study, a trypsin inhibitor was purified and characterized from the venom of scorpion Mesobuthus eupeus, which enhanced the biological activities of crude venom components in mice when injected in combination with crude venom. This protease inhibitor, named MeKTT-1, belonged to Kunitz-type toxins subfamily. Native MeKTT-1 selectively inhibited trypsin with a Kivalue of 130 nmol·L⁻¹. Furthermore, MeKTT-1 was shown to be a thermo-stable peptide. In animal behavioral tests, MeKTT-1 prolonged the pain behavior induced by scorpion crude venom, suggesting that protease inhibitors in scorpion venom inhibited proteases and protect the functionally important peptide/protein toxins from degradation, consequently keeping them active longer. In conclusion, this was the first experimental evidence about the natural existence of serine protease inhibitor in the venom of scorpion Mesobuthus eupeus, which preserved the activity of venom components, suggests that scorpions may use protease inhibitors for survival.
    Full-text · Article · Aug 2016
    • "Among all PIs, serine protease inhibitors are the largest and most widely distributed superfamily of PIs [4][5][6]. Serine protease inhibitors (SPIs) are ubiquitous in animals, plants as well as microorganisms and they play important roles in physiological processes such as blood coagulation, tissue remodeling, and proteolysis regulation [7][8][9][10]. According to previous reports, SPIs have been found in a variety of animal venoms, including snakes, scorpions, spider, cnidarians, cone snails, platypus, and hymenopterans, as well as the salivary secretions of hematophagous insects and leeches [11][12][13]. "
    [Show abstract] [Hide abstract] ABSTRACT: Protease inhibitors (PIs) are proteins or peptides capable of inhibiting the catalytic activity of proteolytic enzymes. They are widely distributed in nature and can be found in all kingdoms of cellular life and also in viral genomes. It has previously been stated that a typical mammalian genome contains 2%–4% of genes encoding for proteases or protease inhibitors, indicating the importance of proteolysis in their biological processes. However, many protease inhibitors have been reported to be present in animal venoms, suggesting that venomous animals use these proteins/peptides in their biological process of survival. Similarly, in recent years, some protease inhibitors have been reported to be present in scorpions and most of them have been identified by cDNA library screening or transcriptomic analysis. These protease inhibitors identified from scorpions have been described in two classes, such as 1) Kunitz-type inhibitors, and 2) Ascaris type inhibitors. Therefore, all the protease inhibitors identified to date from scorpions should be compiled based on their functional categories to help further understanding and research. Here, on the basis of published reports, this review describes about functions, primary sequences, structures, molecular mechanisms as well as functional diversity of the proteins/peptides from scorpions which have been reported to act as protease inhibitors. Summarily, here, we provide updated as well as amassed information about the scorpion protease inhibitors.
    Full-text · Article · Mar 2016
    • "pro-thrombotic functions of NSP. Serpins are suicide inhibitors forming 1:1 stoichiometric complexes wherein the protease cleaves the serpin RCL P1-P1' scissile bond, forming a complex with the serpin such that both the serpin and protease lose function after binding1234529]. These active peptides may represent a class of anti-inflammatory peptides similar to the highly active expanding classes of defensin peptides. "
    [Show abstract] [Hide abstract] ABSTRACT: Serpins regulate coagulation and inflammation, binding serine proteases in suicide inhibitory complexes. Target proteases cleave the serpin reactive center loop (RCL) scissile P1-P1' bond resulting in serpin-protease suicide inhibitory complexes. This inhibition requires a near full-length serpin sequence. Myxomavirus Serp-1 inhibits thrombolytic and thrombotic proteases while mammalian neuroserpin (NSP) inhibits only thrombolytic proteases. Both serpins markedly reduce arterial inflammation and plaque in rodent models after single dose infusion. In contrast Serp-1 but not NSP improves survival in a lethal murine gammaherpesvirus68 (MHV68) infection in interferon gamma receptor deficient mice (IFNγR-/-). Serp-1 has also been successfully tested in a Phase 2a clinical trial. We postulated that proteolytic cleavage of the RCL produces active peptide derivatives with expanded function. Eight peptides encompassing predicted protease cleavage sites for Serp-1 and NSP were synthesized and tested for inhibitory function in vitro and in vivo. In engrafted aorta, selected peptides containing R or RN, not RM, with 0 or +1 charge, significantly reduced plaque. Conversely, S-6 a hydrophobic peptide of NSP, lacking R or RN with -4 charge, induced early thrombosis and mortality. S-1 and S-6 also significantly reduced CD11b+ monocyte counts in mouse splenocytes. S-1 peptide had increased efficacy in PAI-1 serpin deficient transplants. Plaque reduction correlated with mononuclear cell activation..In a separate study Serp-1 peptide, S-7 improved survival in the MHV68 vasculitis model whereas an inverse S-7 peptide was inactive. Reactive center peptides derived from Serp-1 and NSP with suitable charge and hydrophobicity have the potential to extend immunomodulatory functions of serpins.
    Full-text · Article · Nov 2015
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