Serpins: structure, function and molecular evolution
ABSTRACT 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.
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ABSTRACT: Imbalanced protease activity has long been recognized in the progression of disease states such as cancer and inflammation. Serpins, the largest family of endogenous protease inhibitors, target a wide variety of serine and cysteine proteases and play a role in a number of physiological and pathological states. The expression profiles of 20 serpins and 105 serine and cysteine proteases were determined across a panel of normal and diseased human tissues. In general, expression of serpins was highly restricted in both normal and diseased tissues, suggesting defined physiological roles for these protease inhibitors. A high correlation in expression for a particular serpin-protease pair in healthy tissues was often predictive of a biological interaction. The most striking finding was the dramatic change observed in the regulation of expression between proteases and their cognate inhibitors in diseased tissues. The loss of regulated serpin-protease matched expression may underlie the imbalanced protease activity observed in pathological states.Genomics 09/2006; 88(2):173-84. DOI:10.1016/j.ygeno.2006.03.017 · 2.79 Impact Factor
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ABSTRACT: This study aimed to detect potential serum biomarkers for gastric cancer. In the present study, we used magnetic bead-based purification and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to detect potential serum markers in 70 gastric cancer (GC) patients compared with 72 healthy controls. On average, up to 81 peaks, of which 11 were significantly different m/z peaks (fold change >1.5; P < 0.001, Wilcoxon rank sum test) between GC group and healthy controls were detected. Two potential gastric serum biomarkers (m/z values of 1546.02 and 5335.08), with higher and specific expression in GC patients were further identified as peptide regions of SERPINA1 and ENOSF1. Enzyme-linked immunosorbent assays (ELISAs) were used to analyze 210 additional serum samples obtained from 36 healthy volunteers, 36 GC patients, 30 GU patients, 36 nonsmall-cell lung cancer (NSCLC) patients, 36 clear-cell renal cell carcinoma (CCRCC) patients, and 36 pancreatic cancer patients to verify the expression of SERPINA1 and ENOSF1 in GC sera. The suitability of the present method for gastric serum proteomic analysis was demonstrated and led to the identification of two peptide regions and their corresponding proteins as potential serum biomarkers for the serum detection of GC.Tumor Biology 02/2015; DOI:10.1007/s13277-015-3163-2 · 2.84 Impact Factor
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ABSTRACT: Serine proteinase inhibitors (Serpins) are a large superfamily of structurally related, but functionally diverse proteins that control essential proteolytic pathways in most branches of life. Given their importance in the biology of many organisms, the concept that ticks might utilize serpins to evade host defenses and immunizing against or disrupting their functions as targets for tick control is an appealing option. A sequence homology search strategy has allowed us to identify at least 45 tick serpin genes in the Ixodes scapularis genome that are structurally segregated into 32 intronless and 13 intron-containing genes. Nine of the intron-containing serpins occur in a cluster of 11 genes that span 170 kb of DNA sequence. Based on consensus amino acid residues in the reactive center loop (RCL) and signal peptide scanning, 93% are putatively inhibitory while 82% are putatively extracellular. Among the 11 different amino acid residues that are predicted at the P1 sites, 16 sequences possess basic amino acid (R/K) residues. Temporal and spatial expression analyses revealed that 40 of the 45 serpins are differentially expressed in salivary glands (SG) and/or midguts (MG) of unfed and partially fed ticks. Ten of the 38 serpin genes were expressed from six to 24 hrs of feeding while six and fives genes each are predominantly or exclusively expressed in either MG and SG respectively. Given the diversity among tick species, sizes of tick serpin families are likely to be variable. However this study provides insight on the potential sizes of serpin protein families in ticks. Ticks must overcome inflammation, complement activation and blood coagulation to complete feeding. Since these pathways are regulated by serpins that have basic residues at their P1 sites, we speculate that I. scapularis may utilize some of the serpins reported in this study to manipulate host defense. We have discussed our data in the context of advances on the molecular physiology of I. scapularis. Although the paper is descriptive, this study provides the first step toward a comprehensive understanding of serpins in tick physiology.BMC Genomics 06/2009; 10(1):217. DOI:10.1186/1471-2164-10-217 · 4.04 Impact Factor