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IUBMB Life May 2009Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsins underwent the most predominant genetic expansion yielding the enzymes... (Review)
Review
Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsins underwent the most predominant genetic expansion yielding the enzymes responsible for digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis, and immunity. The success of this expansion resides in a highly efficient fold that couples catalysis and regulatory interactions. Added complexity comes from the recent observation of a significant conformational plasticity of the trypsin fold. A new paradigm emerges where two forms of the protease, E* and E, are in allosteric equilibrium and determine biological activity and specificity.
Topics: Isoenzymes; Models, Molecular; Protein Binding; Protein Conformation; Serine Endopeptidases; Substrate Specificity
PubMed: 19180666
DOI: 10.1002/iub.186 -
The FEBS Journal May 2023Serine proteases (SPs) constitute a very important family of enzymes, both physiologically and pathologically. The effects produced by these proteins have been explained... (Review)
Review
Serine proteases (SPs) constitute a very important family of enzymes, both physiologically and pathologically. The effects produced by these proteins have been explained by their proteolytic activity. However, the discovery of pharmacologically active SP molecules that show no enzymatic activity, as the so-called pseudo SPs or SP homologs (SPHs), has exposed a profoundly neglected possibility of nonenzymatic functions of these SP molecules. In this review, the most thoroughly described SPHs are presented. The main physiological domains in which SPHs operate appear to be in reproduction, embryonic development, immune response, host defense, and hemostasis. Hitherto unexplained actions of SPs should therefore be considered also as the result of the ligand-like attributes of SPs. The gain of a novel function by an SPH is a consequence of specific amino acid replacements that have resulted in a novel interaction interface or a 'catalytic trap'. Unraveling the SP/SPH interactome will provide a description of previously unknown physiological functions of SPs/SPHs, aiding the creation of innovative medical approaches.
Topics: Serine; Serine Proteases; Serine Endopeptidases; Immunity
PubMed: 35032346
DOI: 10.1111/febs.16355 -
Science Advances Dec 2023Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial...
Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial peptides, respectively, to kill pathogens. These two processes are mediated by phenoloxidase (PO) and Spätzle (Spz) through an extracellular network of serine proteases. While some proteases have been identified in in genetic studies, the exact order of proteolytic activation events remains controversial. Here, we reconstituted the serine protease framework in by biochemical methods. This system comprises 10 proteases, i.e., ModSP, cSP48, Grass, Psh, Hayan-PA, Hayan-PB, Sp7, MP1, SPE and Ser7, which form cascade pathways that recognize microbial molecular patterns and virulence factors, and generate PO1, PO2, and Spz from their precursors. Furthermore, the serpin Necrotic negatively regulates the immune response progression by inhibiting ModSP and Grass. The biochemical approach, when combined with genetic analysis, is crucial for addressing problems that long stand in this important research field.
Topics: Animals; Drosophila; Drosophila melanogaster; Drosophila Proteins; Serine Endopeptidases; Serine Proteases
PubMed: 38117884
DOI: 10.1126/sciadv.adk2756 -
American Journal of Physiology. Lung... May 2017More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary,... (Review)
Review
More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment, or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity, and regulation, including the expression profile of HAT, and discuss its possible roles in respiratory physiology and disease.
Topics: Animals; Biocatalysis; Fetal Development; Humans; Models, Biological; Respiration Disorders; Serine Endopeptidases
PubMed: 28235951
DOI: 10.1152/ajplung.00509.2016 -
The FEBS Journal Sep 2021Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in... (Review)
Review
Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.
Topics: Adipose Tissue; Animals; Cell Differentiation; Gene Expression Regulation; Hepatocyte Growth Factor; Homeostasis; Humans; Kidney; Liver; Mice; Neoplasms; Proto-Oncogene Proteins c-met; Serine Endopeptidases; Serine Proteases
PubMed: 33300264
DOI: 10.1111/febs.15663 -
Frontiers in Immunology 2022During tumor development, invasion and metastasis, the intimate interaction between tumor and stroma shapes the tumor microenvironment and dictates the fate of tumor... (Review)
Review
During tumor development, invasion and metastasis, the intimate interaction between tumor and stroma shapes the tumor microenvironment and dictates the fate of tumor cells. Stromal cells can also influence anti-tumor immunity and response to immunotherapy. Understanding the molecular mechanisms that govern this complex and dynamic interplay, thus is important for cancer diagnosis and therapy. Proteolytic enzymes that are expressed and secreted by both cancer and stromal cells play important roles in modulating tumor-stromal interaction. Among, several serine proteases such as fibroblast activation protein, urokinase-type plasminogen activator, kallikrein-related peptidases, and granzymes have attracted great attention owing to their elevated expression and dysregulated activity in the tumor microenvironment. This review highlights the role of serine proteases that are mainly derived from stromal cells in tumor progression and associated theranostic applications.
Topics: Animals; Carcinogenesis; Endopeptidases; Extracellular Matrix; Granzymes; Humans; Kallikreins; Membrane Proteins; Neoplasms; Precision Medicine; Serine Proteases; Stromal Cells; Tumor Microenvironment; Urokinase-Type Plasminogen Activator
PubMed: 35222418
DOI: 10.3389/fimmu.2022.832418 -
Journal of Thrombosis and Haemostasis :... Oct 2016Thrombin is a multifunctional serine protease produced from prothrombin, and is a key regulator in hemostatic and non-hemostatic processes. It is the main effector... (Review)
Review
Thrombin is a multifunctional serine protease produced from prothrombin, and is a key regulator in hemostatic and non-hemostatic processes. It is the main effector protease in primary hemostasis by activating platelets, and plays a key role in secondary hemostasis. Besides its well-known functions in hemostasis, thrombin also plays a role in various non-hemostatic biological and pathophysiologic processes, predominantly mediated through activation of protease-activated receptors (PARs). Depending on several factors, such as the concentration of thrombin, the duration of activation, the location of PARs, the presence of coreceptors, and the formation of PAR heterodimers, activation of the receptor by thrombin can induce different cellular responses. Moreover, thrombin can have opposing effects in the same cell; it can induce both inflammatory and anti-inflammatory signals. Owing to the complexity of thrombin's signal transduction pathways, the exact mechanism behind the dichotomy of thrombin is yet still unknown. In this review, we highlight the hemostatic and non-hemostatic functions of thrombin, and specifically focus on the non-hemostatic dual role of thrombin under various conditions and in relation to cardiovascular disease.
Topics: Animals; Blood Coagulation; Blood Platelets; Cardiovascular Diseases; Hemostasis; Humans; Inflammation; Platelet Activation; Protein Multimerization; Receptors, Proteinase-Activated; Receptors, Thrombin; Serine Endopeptidases; Serine Proteases; Signal Transduction; Thrombin; Transcriptional Activation
PubMed: 27513692
DOI: 10.1111/jth.13441 -
Frontiers in Cellular and Infection... 2021The pathobiont causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes... (Review)
Review
The pathobiont causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.
Topics: Humans; Otitis Media; Pneumococcal Infections; Serine Endopeptidases; Streptococcus pneumoniae; Subtilisin; Trypsin
PubMed: 34790590
DOI: 10.3389/fcimb.2021.763152 -
Viruses Jan 2019Many plant viruses express their proteins through a polyprotein strategy, requiring the acquisition of protease domains to regulate the release of functional mature... (Review)
Review
Many plant viruses express their proteins through a polyprotein strategy, requiring the acquisition of protease domains to regulate the release of functional mature proteins and/or intermediate polyproteins. Positive-strand RNA viruses constitute the vast majority of plant viruses and they are diverse in their genomic organization and protein expression strategies. Until recently, proteases encoded by positive-strand RNA viruses were described as belonging to two categories: (1) chymotrypsin-like cysteine and serine proteases and (2) papain-like cysteine protease. However, the functional characterization of plant virus cysteine and serine proteases has highlighted their diversity in terms of biological activities, cleavage site specificities, regulatory mechanisms, and three-dimensional structures. The recent discovery of a plant picorna-like virus glutamic protease with possible structural similarities with fungal and bacterial glutamic proteases also revealed new unexpected sources of protease domains. We discuss the variety of plant positive-strand RNA virus protease domains. We also highlight possible evolution scenarios of these viral proteases, including evidence for the exchange of protease domains amongst unrelated viruses.
Topics: Cysteine Endopeptidases; Evolution, Molecular; Peptide Hydrolases; Plant Viruses; Polyproteins; RNA Viruses; Serine Endopeptidases; Serine Proteases; Viral Proteins
PubMed: 30650571
DOI: 10.3390/v11010066 -
Biological & Pharmaceutical Bulletin 2022Vibrio vulnificus is a Gram-negative estuarine bacterium that causes infection in immuno-compromised patients, eels, and shrimp. V. vulnificus NCIMB2137, a...
Vibrio vulnificus is a Gram-negative estuarine bacterium that causes infection in immuno-compromised patients, eels, and shrimp. V. vulnificus NCIMB2137, a metalloprotease-negative strain isolated from a diseased eel, produces a 45-kDa chymotrypsin-like alkaline serine protease known as VvsA. The gene encoding vvsA also includes another gene, vvsB with an unknown function; however, it is assumed to be an essential molecular chaperone for the maturation of VvsA. In the present study, we used an in vitro cell-free translation system to examine the maturation pathway of VvsA. We individually expressed the vvsA and vvsB genes and detected their mRNAs. However, the sample produced from vvsA did not exhibit protease activity. A sodium dodecyl sulfate (SDS) analysis detected the VvsB protein, but not the VvsA protein. A Western blotting analysis using a histidine (His)-tag at the amino terminus of proteins also showed no protein production by vvsA. These results suggested the translation, but not the transcription of vvsA. Factors derived from Escherichia coli were used in the in vitro cell-free translation system employed in the present study. The operon of the serine protease gene containing vvsA and vvsB was expressed in E. coli. Although serine proteases were produced, they were cleaved at different sites and no active mature forms were detected. These results indicate that the operon encoding vvsA and vvsB is a gene constructed to be specifically expressed in V. vulnificus.
Topics: Humans; Vibrio vulnificus; Serine Proteases; Escherichia coli; Serine Endopeptidases
PubMed: 36328494
DOI: 10.1248/bpb.b22-00106