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Methods (San Diego, Calif.) Feb 2004One of the more common features of serpins is the ability to bind various ligands. Ligand binding can occur so that the inhibitory properties of the serpin are... (Review)
Review
One of the more common features of serpins is the ability to bind various ligands. Ligand binding can occur so that the inhibitory properties of the serpin are regulated, so that the serpin can be localized, or to produce or modulate some other biological function of the serpin. Ligands known to affect serpin biologic activity include glycosaminoglycans such as heparin, heparan sulfate and dermatan sulfate, DNA, extracellular matrix proteins such as vitronectin and collagen, and small organic molecule hormones. Many different biochemical and biophysical techniques in conjunction with molecular biology and cell biology approaches have been used to study the binding of various ligands to serpins and to assess the influence of this binding on activity and structure. We summarize here the different approaches that have been used to identify serpin ligands and the many methods that have been used to characterize the interactions of these ligands with their cognate serpins.
Topics: Binding Sites; Calorimetry; Chromatography, Affinity; Chromatography, Gel; Collodion; Crystallography, X-Ray; Electrophoresis; Electrophoretic Mobility Shift Assay; Endopeptidases; Gene Library; Genes, Reporter; Kinetics; Ligands; Protein Binding; Protein Conformation; Serpins; Spectrum Analysis; Ultracentrifugation
PubMed: 14698622
DOI: 10.1016/s1046-2023(03)00201-9 -
Oncology Reports Sep 2021Serine proteinase inhibitor B9 (serpin B9) is a member of the serine protease inhibitor superfamily, which is widely found in animals, plants and microorganisms.... (Review)
Review
Serine proteinase inhibitor B9 (serpin B9) is a member of the serine protease inhibitor superfamily, which is widely found in animals, plants and microorganisms. Serpin B9 has been reported to protect cells from the immune‑killing effect of granzyme B (GrB) released by lymphocytes. In recent years, an increasing number of studies have indicated that serpin B9 is involved in tumour apoptosis, immune evasion, tumorigenesis, progression, metastasis, drug resistance and even in maintaining the stemness of cancer stem cells (CSCs). Moreover, according to clinical studies, serpin B9 has been demonstrated to be significantly associated with the development of precancerous lesions, a poor prognosis and ineffective therapies, suggesting that serpin B9 may be a potential target for cancer treatment and an indicator of cancer diagnosis; thus, it has begun to attract increased attention from scholars. The present review concisely described the structure and biological functions of the serpin superfamily and serpin B9. In addition, related research on serpins in cancer is discussed in order to provide a comprehensive understanding of the role of serpin B9 in cancer, as well as its clinical significance for cancer diagnosis and prognosis.
Topics: Animals; Antineoplastic Agents; Apoptosis; Gene Expression Regulation, Neoplastic; Granzymes; Humans; Immune System; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Prognosis; Serine Proteinase Inhibitors; Serpins
PubMed: 34278491
DOI: 10.3892/or.2021.8141 -
CNS Neuroscience & Therapeutics Jul 2023Serpin is a superfamily of serine proteinase inhibitors. They have anticoagulative activities and immunoregulatory effects. The family has been widely studied in stroke... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Serpin is a superfamily of serine proteinase inhibitors. They have anticoagulative activities and immunoregulatory effects. The family has been widely studied in stroke patients and animal stroke models. However, results from clinical and preclinical studies are controversial. The systematic review and meta-analysis aimed to determine whether serpin activities are affected by stroke and whether members of the serpin family could be used in stroke treatment.
METHODS
Literature was systematically searched in six databases until September 5, 2022. In the included studies, 47 clinical studies (8276 subjects) reported concentrations of serpin proteins in stroke patients and healthy controls. In total, 41 preclinical studies (742 animals) reported neurological outcomes in animal models with serpin treatment and vehicle.
RESULTS
Meta-analysis of clinical studies showed that both ischemic (IS) and hemorrhagic stroke patients had higher thrombin-antithrombin complex (TAT) levels and lower antithrombin (AT) levels which were persistent in the acute and subacute phase of IS. Meta-analysis of preclinical studies reported the efficacy of serpins in treating stroke. C1-INH and FUT175 reduced brain infarct size and improved sensorimotor and motor behavior in a dose- and time-dependent manner in the MCAO models.
CONCLUSIONS
Our study confirmed the important roles serpin family proteins played in the onset, progression, and treatment of stroke. Among serpins, AT and TAT may be used as blood biomarkers in the early diagnosis of stroke. C1-INH and FUT175 could be potential medications for IS.
Topics: Animals; Serpins; Biomarkers; Models, Animal; Stroke
PubMed: 37017398
DOI: 10.1111/cns.14205 -
Journal of Experimental Botany Apr 2019The serpins are a family of structurally conserved protease inhibitors found in all animal and plant kingdoms. After interaction with their cognate substrate(s), their... (Review)
Review
The serpins are a family of structurally conserved protease inhibitors found in all animal and plant kingdoms. After interaction with their cognate substrate(s), their native energetically stressed state is relaxed by hydrolysis, resulting in a semi-stable covalent bond that disables the protease. The inherent flexible serpin structure supports additional non-inhibitory functions. This review will focus on several biological functions attributed to plant serpins, ranging from specific cell death protease inhibitors to a stabilizing role for β-amylase in seeds. Functional conservation of a particular serpin type, the LR serpins, is suggested by its compelling ubiquity throughout the plant kingdom. The multiple target specificity of plant serpins including the LR serpins enables them to perform dual functions that are not mutually exclusive both as a regulator of cell death and as a protective anti-pathogenic protein.
Topics: Plant Proteins; Plants; Protease Inhibitors; Serpins
PubMed: 30721992
DOI: 10.1093/jxb/ery460 -
Journal of Thrombosis and Haemostasis :... Jul 2011Serpins have been studied as a distinct protein superfamily since the early 80s. In spite of the poor sequence homology between family members, serpins share a highly... (Review)
Review
Serpins have been studied as a distinct protein superfamily since the early 80s. In spite of the poor sequence homology between family members, serpins share a highly conserved core structure that is critical for their functioning as serine protease inhibitors. Therefore, discoveries made about one serpin can be related to the others. In this short review, I introduce the serpin structure and general mechanism of protease inhibition, and illustrate, using recent crystallographic and biochemical data on antithrombin (AT), how serpin activity can be modulated by cofactors. The ability of the serpins to undergo conformational change is critical for their function, but it also renders them uniquely susceptible to mutations that perturb their folding, leading to deficiency and disease. A recent crystal structure of an AT dimer revealed that serpins can participate in large-scale domain-swaps to form stable polymers, and that such a mechanism may explain the accumulation of misfolded serpins within secretory cells. Serpins play important roles in haemostasis and fibrinolysis, and although each will have some elements specifically tailored for its individual function, the mechanisms described here provide a general conceptual framework.
Topics: Humans; Models, Molecular; Serpins; Structure-Activity Relationship
PubMed: 21781239
DOI: 10.1111/j.1538-7836.2011.04360.x -
Methods in Enzymology 2011Serpins (serine protease inhibitors) have traditionally been grouped together based on structural homology. They share common structural features of primary sequence,...
Serpins (serine protease inhibitors) have traditionally been grouped together based on structural homology. They share common structural features of primary sequence, but not all serpins require binding to cofactors in order to achieve maximal protease inhibition. In order to obtain physiologically relevant rates of inhibition of target proteases, some serpins utilize the unbranched sulfated polysaccharide chains known as glycosaminoglycans (GAGs) to enhance inhibition. These GAG-binding serpins include antithrombin (AT), heparin cofactor II (HCII), and protein C inhibitor (PCI). The GAGs heparin and heparan sulfate have been shown to bind AT, HCII, and PCI, while HCII is also able to utilize dermatan sulfate as a cofactor. Other serpins such as PAI-1, kallistatin, and α(1)-antitrypsin also interact with GAGs with different endpoints, some accelerating protease inhibition while others inhibit it. There are many serpins that bind or carry ligands that are unrelated to GAGs, which are described elsewhere in this work. For most GAG-binding serpins, binding of the GAG occurs in a conserved region of the serpin near or involving helix D, with the exception of PCI, which utilizes helix H. The binding of GAG to serpin can lead to a conformational change within the serpin, which can lead to increased or tighter binding to the protease, and can accelerate the rates of inhibition up to 10,000-fold compared to the unbound native serpin. In this chapter, we will discuss three major GAG-binding serpins with known physiological roles in modulating coagulation: AT (SERPINC1), HCII (SERPIND1), and PCI (SERPINA5). We will review methodologies implemented to study the structure of these serpins and those used to study their interactions with GAG's. We discuss novel techniques to examine the serpin-GAG interaction and finally we review the biological roles of these serpins by describing the mouse models used to study them.
Topics: Animals; Antithrombin III; Binding Sites; Blood Coagulation; Chemistry Techniques, Analytical; Dermatan Sulfate; Heparin; Heparin Cofactor II; Humans; Kinetics; Mice; Mice, Knockout; Models, Molecular; Molecular Biology; Plasminogen Activator Inhibitor 1; Protein Binding; Protein C Inhibitor; Protein Structure, Secondary; Species Specificity; Thrombin; alpha 1-Antitrypsin
PubMed: 22078533
DOI: 10.1016/B978-0-12-385950-1.00007-9 -
International Journal of Molecular... Jun 2021Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a protease-antiprotease imbalance. In COPD, the relationship between the neutrophil serine protease, neutrophil elastase, and its endogenous inhibitor, alpha-1-antitrypsin (AAT) is the best characterised. AAT belongs to a superfamily of serine protease inhibitors known as serpins. Advances in screening technologies have, however, resulted in many members of the serpin superfamily being identified as having differential expression across a multitude of chronic lung diseases compared to healthy individuals. Serpins exhibit a unique suicide-substrate mechanism of inhibition during which they undergo a dramatic conformational change to a more stable form. A limitation is that this also renders them susceptible to disease-causing mutations. Identification of the extent of their physiological/pathological role in the airways would allow further expansion of knowledge regarding the complexity of protease regulation in the lung and may provide wider opportunity for their use as therapeutics to aid the management of COPD and other chronic airways diseases.
Topics: Animals; Disease Models, Animal; Humans; Pulmonary Disease, Chronic Obstructive; Serine Proteases; Serpins
PubMed: 34198546
DOI: 10.3390/ijms22126351 -
Biomolecules Jan 2022Regulation of the equilibrium between proteases and their inhibitors is fundamental to health maintenance. Consequently, developing a means of targeting protease... (Review)
Review
Regulation of the equilibrium between proteases and their inhibitors is fundamental to health maintenance. Consequently, developing a means of targeting protease activity to promote tissue regeneration and inhibit inflammation may offer a new strategy in therapy development for diabetes and other diseases. Specifically, recent efforts have focused on serine protease inhibitors, known as serpins, as potential therapeutic targets. The serpin protein family comprises a broad range of protease inhibitors, which are categorized into 16 clades that are all extracellular, with the exception of Clade B, which controls mostly intracellular proteases, including both serine- and papain-like cysteine proteases. This review discusses the most salient, and sometimes opposing, views that either inhibition or augmentation of protease activity can bring about positive outcomes in pancreatic islet biology and inflammation. These potential discrepancies can be reconciled at the molecular level as specific proteases and serpins regulate distinct signaling pathways, thereby playing equally distinct roles in health and disease development.
Topics: Animals; Diabetes Mellitus; Humans; Peptide Hydrolases; Serpins; Signal Transduction
PubMed: 35053215
DOI: 10.3390/biom12010067 -
Chemical Reviews Dec 2002
Review
Topics: Animals; Binding Sites; Crystallography, X-Ray; Endopeptidases; Humans; Plant Proteins; Protein Binding; Protein Conformation; Protein Folding; Serine Proteinase Inhibitors; Serpins; Viral Proteins
PubMed: 12475206
DOI: 10.1021/cr010170+ -
Methods in Enzymology 2011Over the past 19 years, we have developed a novel myxoma virus-derived anti-inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory... (Review)
Review
Over the past 19 years, we have developed a novel myxoma virus-derived anti-inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory therapeutic. This review will describe the initial identification of viral serpins with anti-inflammatory potential, beginning with preclinical analysis of viral pathogenesis and proceeding to cell and molecular target analyses, and successful clinical trial. The central aim of this review is to describe the development of two serpins, Serp-1 and Serp-2, as a new class of immune modulating drug, from inception to implementation. We begin with an overview of the approaches used for successful mining of the virus for potential serpin immunomodulators in viruses. We then provide a methodological overview of one inflammatory animal model used to test for serpin anti-inflammatory activity followed by methods used to identify cells in the inflammatory response system targeted by these serpins and molecular responses to serpin treatment. Finally, we provide an overview of our findings from a recent, successful clinical trial of the secreted myxomaviral serpin, Serp-1, in patients with unstable inflammatory coronary arterial disease.
Topics: Animals; Anti-Inflammatory Agents; Clinical Trials as Topic; Humans; Mice; Serpins; Viruses
PubMed: 21683260
DOI: 10.1016/B978-0-12-386471-0.00015-8