scholarly journals Distinct encounter complexes of PAI-1 with plasminogen activators and vitronectin revealed by changes in the conformation and dynamics of the reactive center loop

2015 ◽  
Vol 25 (2) ◽  
pp. 499-510 ◽  
Author(s):  
Tihami Qureshi ◽  
Sumit Goswami ◽  
Carlee S. McClintock ◽  
Matthew T. Ramsey ◽  
Cynthia B. Peterson
Keyword(s):  
Plasminogen Activators ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Pai 1

The Reactive-center Loop of Active PAI-1 is Folded Close to the Protein Core and can be Partially Inserted

2004 ◽  
Vol 335 (3) ◽  
pp. 823-832 ◽  
Author(s):  
Peter Hägglöf ◽  
Fredrik Bergström ◽  
Malgorzata Wilczynska ◽  
Lennart B.-Å Johansson ◽  
Tor Ny
Keyword(s):  
Protein Core ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Pai 1

scholarly journals The Omptins of Yersinia pestis and Salmonella enterica Cleave the Reactive Center Loop of Plasminogen Activator Inhibitor 1

2010 ◽  
Vol 192 (18) ◽  
pp. 4553-4561 ◽  
Author(s):  
Johanna Haiko ◽  
Liisa Laakkonen ◽  
Katri Juuti ◽  
Nisse Kalkkinen ◽  
Timo K. Korhonen
Keyword(s):  
Yersinia Pestis ◽  
Plasminogen Activator ◽  
Salmonella Enterica ◽  
Yersinia Pseudotuberculosis ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Reactive Center Loop ◽  
Reactive Center ◽  
Activator Inhibitor ◽  
Pai 1

ABSTRACT Plasminogen activator inhibitor 1 (PAI-1) is a serine protease inhibitor (serpin) and a key molecule that regulates fibrinolysis by inactivating human plasminogen activators. Here we show that two important human pathogens, the plague bacterium Yersinia pestis and the enteropathogen Salmonella enterica serovar Typhimurium, inactivate PAI-1 by cleaving the R346-M347 bait peptide bond in the reactive center loop. No cleavage of PAI-1 was detected with Yersinia pseudotuberculosis, an oral/fecal pathogen from which Y. pestis has evolved, or with Escherichia coli. The cleavage and inactivation of PAI-1 were mediated by the outer membrane proteases plasminogen activator Pla of Y. pestis and PgtE protease of S. enterica, which belong to the omptin family of transmembrane endopeptidases identified in Gram-negative bacteria. Cleavage of PAI-1 was also detected with the omptins Epo of Erwinia pyrifoliae and Kop of Klebsiella pneumoniae, which both belong to the same omptin subfamily as Pla and PgtE, whereas no cleavage of PAI-1 was detected with omptins of Shigella flexneri or E. coli or the Yersinia chromosomal omptins, which belong to other omptin subfamilies. The results reveal a novel serpinolytic mechanism by which enterobacterial species expressing omptins of the Pla subfamily bypass normal control of host proteolysis.

Factors Involved In the Plasminogen Activation System in Human Breast Tumours

1994 ◽  
Vol 71 (05) ◽  
pp. 684-691 ◽  
Author(s):  
László Damjanovich ◽  
Csaba Turzó ◽  
Róza Ádány
Keyword(s):  
Epithelial Cells ◽  
Connective Tissue ◽  
Plasminogen Activators ◽  
Breast Tumour ◽  
Plasminogen Activation ◽  
Malignant Tumours ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Malignant Breast ◽  
Pai 1

SummaryThe plasminogen activation system is a delicately balanced assembly of enzymes which seems to have primary influence on tumour progression. The conversion of plasminogen into serine protease plasmin with fibrinolytic activity depends on the actual balance between plasminogen activators (urokinase type; u-PA and tissue type; t-PA) and their inhibitors (type 1 and 2 plasminogen activator inhibitors; PAI-1 and PAI-2). The purpose of this study was to determine the exact histological localization of all the major factors involved in plasminogen activation, and activation inhibition (plasmin system) in benign and malignant breast tumour samples. Our results show that factors of the plasmin system are present both in benign and malignant tumours. Cancer cells strongly labelled for both u-PA and t-PA, but epithelial cells of fibroadenoma samples were also stained for plasminogen activators at least as intensively as tumour cells in cancerous tissues. In fibroadenomas, all the epithelial cells were labelled for PAM. Staining became sporadic in malignant tumours, cells located at the periphery of tumour cell clusters regularly did not show reaction for PAI-1. In the benign tumour samples the perialveolar connective tissue stroma contained a lot of PAI-1 positive cells, showing characteristics of fibroblasts; but their number was strongly decreased in the stroma of malignant tumours. These findings indicate that the higher level of u-PA antigen, detected in malignant breast tumour samples by biochemical techniques, does not necessarily indicate increased u-PA production by tumour cells but it might be owing to the increased number of cells producing u-PA as well. In malignant tumours PAI-1 seems to be decreased in the frontage of malignant cell invasion; i.e. malignant cells at the host/tumour interface do not express PAI-1 in morphologically detectable quantity and in the peritumoural connective tissue the number of fibroblasts containing PAI-1 is also decreased.

scholarly journals Serpin reactive center loop mobility is required for inhibitor function but not for enzyme recognition.

1994 ◽  
Vol 269 (44) ◽  
pp. 27657-27662 ◽  
Author(s):  
D A Lawrence ◽  
S T Olson ◽  
S Palaniappan ◽  
D Ginsburg
Keyword(s):  
Reactive Center Loop ◽  
Reactive Center ◽  
Enzyme Recognition

A reactive center loop–based prediction platform to enhance the design of therapeutic SERPINs

2021 ◽  
Vol 118 (45) ◽  
pp. e2108458118
Author(s):  
Wariya Sanrattana ◽  
Thibaud Sefiane ◽  
Simone Smits ◽  
Nadine D. van Kleef ◽  
Marcel H. Fens ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Serine Proteases ◽  
Protein C ◽  
Activated Protein C ◽  
Reactive Center Loop ◽  
Physiological Processes ◽  
Naturally Occurring ◽  
Reactive Center ◽  
Insight Into

Serine proteases are essential for many physiological processes and require tight regulation by serine protease inhibitors (SERPINs). A disturbed SERPIN–protease balance may result in disease. The reactive center loop (RCL) contains an enzymatic cleavage site between the P1 through P1’ residues that controls SERPIN specificity. This RCL can be modified to improve SERPIN function; however, a lack of insight into sequence–function relationships limits SERPIN development. This is complicated by more than 25 billion mutants needed to screen the entire P4 to P4’ region. Here, we developed a platform to predict the effects of RCL mutagenesis by using α1-antitrypsin as a model SERPIN. We generated variants for each of the residues in P4 to P4’ region, mutating them into each of the 20 naturally occurring amino acids. Subsequently, we profiled the reactivity of the resulting 160 variants against seven proteases involved in coagulation. These profiles formed the basis of an in silico prediction platform for SERPIN inhibitory behavior with combined P4 to P4’ RCL mutations, which were validated experimentally. This prediction platform accurately predicted SERPIN behavior against five out of the seven screened proteases, one of which was activated protein C (APC). Using these findings, a next-generation APC-inhibiting α1-antitrypsin variant was designed (KMPR/RIRA; / indicates the cleavage site). This variant attenuates blood loss in an in vivo hemophilia A model at a lower dosage than the previously developed variant AIKR/KIPP because of improved potency and specificity. We propose that this SERPIN-based RCL mutagenesis approach improves our understanding of SERPIN behavior and will facilitate the design of therapeutic SERPINs.

scholarly journals Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices

2001 ◽  
Vol 114 (5) ◽  
pp. 917-930 ◽  
Author(s):  
G.E. Davis ◽  
K.A. Pintar ◽  
Allen, R. Salazar ◽  
S.A. Maxwell
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Plasminogen Activators ◽  
Collagen Matrices ◽  
Collagen Gel Contraction ◽  
Blocking Antibodies ◽  
Pai 1

Here, we describe a new function for plasmin and matrix metalloproteinases (MMPs), which is to regulate the regression of capillary tubes in three-dimensional extracellular matrix environments. Using a well-described capillary morphogenesis system in three-dimensional collagen matrices, a new model of capillary regression has been established by adding plasminogen to the culture medium. Plasminogen is converted to plasmin by endothelial cell plasminogen activators which then induces matrix metalloproteinase-dependent collagen gel contraction and capillary regression. Plasminogen addition results in activation of MMP-1 and MMP-9, which then results in collagen proteolysis followed by capillary regression. The endothelial cells undergo apoptosis following gel contraction as detected by flow cytometric analysis as well as by detectable caspase-3 cleavage and caspase-dependent cleavage of the actin cytoskeletal regulatory protein, gelsolin. In addition, directly correlating with the contraction response, tyrosine phosphorylation of p130cas, an adapter protein in the focal adhesion complex, is observed followed by disappearance of the protein. Proteinase inhibitors that block MMPs (TIMP-1 or TIMP-2), plasminogen activators (PAI-1) or plasmin (aprotinin) completely block the gel contraction and regression process. In addition, chemical inhibitors of MMPs that block capillary regression also block MMP-1 and MMP-9 activation suggesting that a key element in this regression response is the molecular control of MMP activation by endothelial cells. Blocking antibodies directed to MMP-1 or MMP-9 interfere with capillary regression while blocking antibodies directed to PAI-1 accelerate capillary regression suggesting that endogenous synthesis of PAI-1 negatively regulates this process. These data present a novel system to study a new mechanism that may regulate regression of capillary tubes, namely, plasmin and MMP-mediated degradation of extracellular matrix.

scholarly journals O ρόλος των ενεργοποιών του πλασμινογόνου και της πλασμίνης στην αναπαραγωγή των θηλαστικών

2017 ◽  
Vol 63 (2) ◽  
pp. 113
Author(s):  
M. TSANTARLIOTOU (Μ. ΤΣΑΝΤΑΡΛΙΩΤΟΥ) ◽  
V. SAPANIDOU (Β.ΣΑΠΑΝΙΔΟΥ) ◽  
I. ZERVOS (Ι. ΖΕΡΒΟΣ) ◽  
S. LAVRENTIADOU (Σ. ΛΑΥΡΕΝΤΙΑΔΟΥ) ◽  
I. TAITZOGLOU (Ι. ΤΑΪΤΖΟΓΛΟΥ) ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Early Stage ◽  
Ovarian Tissue ◽  
Plasminogen Activators ◽  
Tissue Type ◽  
Pharmacological Intervention ◽  
Luteal Regression ◽  
Mammalian Fertilization ◽  
Pai 1

The current knowledge of the role of local and directed fibrinolysis controlled by plasminogen activators (PAs) and regulated by plasminogen activator inhibitors (PAls) in reproduction is summarized. The PA system has been found to play an important role in spermatogenesis in testis and modulation of sperm maturation in epididymis while a lot of studies indicate a role for sperm or seminal plasma PAs in sperm hyperactivation and/or capacitation. Hormoneinduced expression of tissue-type PA (tPA) and PAI-1 in the ovary is involved in the processes of ovulation and luteal regression; increases of urokinase-type PA (uPA) and PAI-1 in the early stage of luteinized follicles may be responsible for ovarian tissue remodeling and angiogenesis. The targeted proteolytic activity plays an essential role in the processes of the cyclic uterine angiogenesis, implantation and placentation as well as in the parturition. As the PA system is involved in multiple phases of mammalian fertilization specific regulatory molecules of this system provide opportunities for pharmacological intervention.

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