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(DABCYL)-Arg-Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2 + H2O
(DABCYL)-Arg + Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2
alpha2-antiplasmin + H2O
?
C3 protein of complement system + H2O
fragments of C3 protein of complement system
-
-
-
?
complement C3 + H2O
?
-
Pla proteolyzes complement C3 which may amiliorate the host inflammatory response by abolishing its chemoattractant properties
-
-
?
complement protein C3 + H2O
?
-
-
-
-
?
D-Val-Leu-Lys-p-nitroanilide + H2O
D-Val-Leu-Lys + p-nitroaniline
human alpha2-antiplasmin + H2O
fragments of alpha2-antiplasmin
-
-
-
-
?
human Glu-plasminogen + H2O
plasmin + ?
-
Pla activates Glu-plasminogen to plasmin, in vitro, TFPI is found to be a much better substrate for Pla than plasminogen
-
-
?
human tissue factor pathway inhibitor + H2O
?
-
Pla can proteolytically degrade TFPI, completely abrogating its anticoagulant function. In vitro, TFPI is found to be a much better substrate for Pla than plasminogen
-
-
?
PAI-1 + H2O
?
a serpin
-
-
?
plasminogen + H2O
plasmin + ?
plasminogen activator inhibitor-1 + H2O
?
serpin alpha2-antiplasmin + H2O
?
-
-
-
-
?
single-chain urokinase + H2O
?
activation
-
-
?
tissue factor pathway inhibitor + H2O
?
YapE + H2O
?
Yersinia pestis autotransporter YapE protein
cleavage of YapE occurs in Yersinia pestis but not in the enteric Yersinia species, and requires the omptin Pla
-
?
YapG + H2O
?
Yersinia pestis autotransporter YapG protein
sites K512, (K548-R549) and K594-R595 represent the primary cleavage sites of YapG, whereas sites K'558 and K'604 represent the secondary alternative cleavage sites
-
?
Yersinia outer proteins + H2O
fragments of Yersinia outer proteins
-
-
-
?
zymogen factor VII + H2O
factor VIIa
-
Pla proteolytically converts zymogen factor VII to the active form, factor VIIa. Pla activates factor VII about twice as fast as it activates plasminogen
-
-
?
additional information
?
-
(DABCYL)-Arg-Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2 + H2O
(DABCYL)-Arg + Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2
-
-
-
?
(DABCYL)-Arg-Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2 + H2O
(DABCYL)-Arg + Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2
-
-
-
?
(DABCYL)-Arg-Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2 + H2O
(DABCYL)-Arg + Arg-Ile-Asn-Arg-Glu-(EDANS)-NH2
-
-
-
?
alpha2-antiplasmin + H2O
?
inactivation
-
-
?
alpha2-antiplasmin + H2O
?
-
Pla inactivates the main physiologic inhibitor of plasmin
-
-
?
alpha2-antiplasmin + H2O
?
-
Pla inactivates alpha2-antiplasmin
-
-
?
alpha2-antiplasmin + H2O
?
a serpin
-
-
?
alpha2-antiplasmin + H2O
?
alpha2AP is the main inhibitor of free plasmin in the circulation. Pla cleaves and inactivates alpha2AP by a single, rapid cut. It appears likely that the R376-M377 bait peptide bond is targeted by Pla
-
-
?
D-Val-Leu-Lys-p-nitroanilide + H2O
D-Val-Leu-Lys + p-nitroaniline
-
Lpa gene encoding a homologue of the plasminogen activator Pla of Yersinia pestis identified, described as a surface protease exhibiting plasminogen activator activity, plasminogen activity of inner and outer membranes measured
-
-
?
D-Val-Leu-Lys-p-nitroanilide + H2O
D-Val-Leu-Lys + p-nitroaniline
-
Lpa gene encoding a homologue of the plasminogen activator Pla of Yersinia pestis identified, described as a surface protease exhibiting plasminogen activator activity, plasminogen activity of inner and outer membranes measured
-
-
?
plasminogen + H2O
plasmin + ?
-
capacity to convert plasminogen into plasmin by the action of the outer-membrane Lpa protein determined
-
-
?
plasminogen + H2O
plasmin + ?
-
capacity to convert plasminogen into plasmin by the action of the outer-membrane Lpa protein determined
-
-
?
plasminogen + H2O
plasmin + ?
-
activates plasminogen by cleaving the Arg560-Val561 bond
-
?
plasminogen + H2O
plasmin + ?
-
-
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
?
plasminogen + H2O
plasmin + ?
-
Pla also expresses a weak coagulase activity
-
?
plasminogen + H2O
plasmin + ?
-
activates plasminogen by cleaving the Arg560-Val561 bond
-
?
plasminogen + H2O
plasmin + ?
-
Pla has the additional ability to bind to the basement membrane component type IV collagen rendering adhesive properties to Yersina pestis cells
-
?
plasminogen + H2O
plasmin + ?
-
Pla belongs to the omptin family of enterobacterial surface proteases and is responsible for the highly efficient invasion of the plague bacterium from the subcutaneous infection site into the circulation
-
-
?
plasminogen + H2O
plasmin + ?
activation
-
-
?
plasminogen + H2O
plasmin + ?
-
plasminogen activator is a surface virulence factor that contributes to the highly imvasive nature of the pathogen by binding various tissue matrix components
-
-
?
plasminogen + H2O
plasmin + ?
-
cleavage of Arg560-/-Val561
-
-
?
plasminogen + H2O
plasmin + ?
identification and analysis of small-peptide substrates and inhibitors of plasminogen activator Pla by use of parallel synthesis and positional scanning
-
-
?
plasminogen + H2O
plasmin + ?
plasminogen activator Pla shown to be essential to cause primary pneumonic plague, minor importance determined for dissemination during pneumonic plague than during bubonic plague, inhibition of plasminogen activator Pla expression shown to prolong survival of infected mice
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
-
-
-
?
plasminogen activator inhibitor-1 + H2O
?
inactivation
-
-
?
plasminogen activator inhibitor-1 + H2O
?
inactivation. PAI-1 is the primary physiological inhibitor of uPA and t-PA and a major inhibitor of fibrinolysis. Pla rapidly inactivates PAI-1 by a single cleavage of the bait peptide at R346-M347. In circulation, most PAI-1 is bound to vitronectin, which is also degraded by Pla
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
PAI-1 is cleaved and inactivated by the Pla protease of Yersinia pestis in the lung airspace of C57BL/6 mice
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
-
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
PAI-1 is cleaved and inactivated by the Pla protease of Yersinia pestis in the lung airspace of C57BL/6 mice
-
-
?
TAFI + H2O
TAFIa + ?
inactivation
-
-
?
TAFI + H2O
TAFIa + ?
TAFI is secreted into plasma as a procarboxypeptidase, it is a regulatory protein linking the coagulation and fibrinolytic systems, and TAFI is protective in septic yersionosis. Pla cleaves at the C-terminal region of TAFI and reduces its activation to TAFIa
-
-
?
tissue factor pathway inhibitor + H2O
?
inactivation
-
-
?
tissue factor pathway inhibitor + H2O
?
TFPI is a major anticoagulant and forms stable TFPI-FXa complexes that block blood clotting. Enzyme Pla cleaves the tissue factor pathway inhibitor, TFPI
-
-
?
additional information
?
-
-
plasminogen activator Pla is essential for the spread of Yersinia pestis from the subcutaneous infection site into circulation, and the proteolytic activation of plasminogen is involved in virulence function. In addition to proteolysis plasminogen activator Pla promotes bacterial adhesion to mammalian extracellular matrices and epithelial cells as well as bacterial invasion into eukayotic cells. Laminin functions as an adhesion target for plasminogen activator Pla, which also expresses a lower adhesion affinity for heparan sulfate proteoglycan. the adhesion targets are not directly degraded by plasminogen activator Pla, but Pla-mediated generation of plasmin leads to their degradation
-
-
?
additional information
?
-
-
plasminogen activator plays a pivotal role in internalisation of bacteria by HeLa cells. Intracellular signalling and cytoskeletal rearrangement is involved in Yersinia pestis plasminogen activator mediated HeLa cell invasion
-
-
?
additional information
?
-
-
no degradation of Val-Leu-Lys-p-nitroanilide. Plasminogen activator degrades outer membrane proteins of Yersinia cell surface and exhibits a weak coagulase activity. In addition to proteolysis plasminogen activator Pla promotes bacterial adhesion to mammalian extracellular matrices and epithelial cells as well as bacterial invasion into eukaryotic cells. Laminin functions as an adhesion target for plasminogen activator Pla, which also expresses a lower adhesion affinity for heparan sulfate proteoglycan. The adhesion targets are not directly degraded by plasminogen activator Pla, but Pla-mediated generation of plasmin leads to their degradation
-
-
?
additional information
?
-
-
the invasion of alveolar macrophages by Yersinia pestis depends both in vitro and in vivo on the expression of plasminogen activator Pla. Macrophages and transfectants expressing C-type lectin receptor DEC-205, but not their negative counterparts, phagocytose plasminogen activator Pla-expressing Yersinia pestis and Escherichia coli K12 more efficiently than Pla-negative controls. The interactions between Pla-expressing bacteria and DEC-205-expressing transfectants or alveolar macrophages can be inhibited by an anti-DEC-205 antibody. The blockage of the Pla-DEC-205 interaction reduces the dissemination of Yersinia pestis in mice
-
-
?
additional information
?
-
the enzyme performs autoproteolysis
-
-
?
additional information
?
-
the enzyme performs autoproteolysis
-
-
?
additional information
?
-
the enzyme performs autoproteolysis
-
-
?
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alpha2-antiplasmin + H2O
?
C3 protein of complement system + H2O
fragments of C3 protein of complement system
-
-
-
-
?
human alpha2-antiplasmin + H2O
fragments of alpha2-antiplasmin
-
-
-
-
?
plasminogen + H2O
plasmin + ?
plasminogen activator inhibitor-1 + H2O
?
single-chain urokinase + H2O
?
activation
-
-
?
TAFI + H2O
TAFIa + ?
TAFI is secreted into plasma as a procarboxypeptidase, it is a regulatory protein linking the coagulation and fibrinolytic systems, and TAFI is protective in septic yersionosis. Pla cleaves at the C-terminal region of TAFI and reduces its activation to TAFIa
-
-
?
tissue factor pathway inhibitor + H2O
?
TFPI is a major anticoagulant and forms stable TFPI-FXa complexes that block blood clotting. Enzyme Pla cleaves the tissue factor pathway inhibitor, TFPI
-
-
?
YapE + H2O
?
Yersinia pestis autotransporter YapE protein
cleavage of YapE occurs in Yersinia pestis but not in the enteric Yersinia species, and requires the omptin Pla
-
?
YapG + H2O
?
Yersinia pestis autotransporter YapG protein
sites K512, (K548-R549) and K594-R595 represent the primary cleavage sites of YapG, whereas sites K'558 and K'604 represent the secondary alternative cleavage sites
-
?
Yersinia outer proteins + H2O
fragments of Yersinia outer proteins
-
-
-
-
?
additional information
?
-
alpha2-antiplasmin + H2O
?
-
Pla inactivates alpha2-antiplasmin
-
-
?
alpha2-antiplasmin + H2O
?
alpha2AP is the main inhibitor of free plasmin in the circulation. Pla cleaves and inactivates alpha2AP by a single, rapid cut. It appears likely that the R376-M377 bait peptide bond is targeted by Pla
-
-
?
plasminogen + H2O
plasmin + ?
-
capacity to convert plasminogen into plasmin by the action of the outer-membrane Lpa protein determined
-
-
?
plasminogen + H2O
plasmin + ?
-
capacity to convert plasminogen into plasmin by the action of the outer-membrane Lpa protein determined
-
-
?
plasminogen + H2O
plasmin + ?
-
activates plasminogen by cleaving the Arg560-Val561 bond
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
?
plasminogen + H2O
plasmin + ?
-
-
-
-
?
plasminogen + H2O
plasmin + ?
-
Pla also expresses a weak coagulase activity
-
-
?
plasminogen + H2O
plasmin + ?
-
activates plasminogen by cleaving the Arg560-Val561 bond
-
-
?
plasminogen + H2O
plasmin + ?
-
Pla has the additional ability to bind to the basement membrane component type IV collagen rendering adhesive properties to Yersina pestis cells
-
-
?
plasminogen + H2O
plasmin + ?
-
Pla belongs to the omptin family of enterobacterial surface proteases and is responsible for the highly efficient invasion of the plague bacterium from the subcutaneous infection site into the circulation
-
-
?
plasminogen + H2O
plasmin + ?
activation
-
-
?
plasminogen + H2O
plasmin + ?
-
plasminogen activator is a surface virulence factor that contributes to the highly imvasive nature of the pathogen by binding various tissue matrix components
-
-
?
plasminogen activator inhibitor-1 + H2O
?
inactivation. PAI-1 is the primary physiological inhibitor of uPA and t-PA and a major inhibitor of fibrinolysis. Pla rapidly inactivates PAI-1 by a single cleavage of the bait peptide at R346-M347. In circulation, most PAI-1 is bound to vitronectin, which is also degraded by Pla
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
PAI-1 is cleaved and inactivated by the Pla protease of Yersinia pestis in the lung airspace of C57BL/6 mice
-
-
?
plasminogen activator inhibitor-1 + H2O
?
-
PAI-1 is cleaved and inactivated by the Pla protease of Yersinia pestis in the lung airspace of C57BL/6 mice
-
-
?
additional information
?
-
-
plasminogen activator Pla is essential for the spread of Yersinia pestis from the subcutaneous infection site into circulation, and the proteolytic activation of plasminogen is involved in virulence function. In addition to proteolysis plasminogen activator Pla promotes bacterial adhesion to mammalian extracellular matrices and epithelial cells as well as bacterial invasion into eukayotic cells. Laminin functions as an adhesion target for plasminogen activator Pla, which also expresses a lower adhesion affinity for heparan sulfate proteoglycan. the adhesion targets are not directly degraded by plasminogen activator Pla, but Pla-mediated generation of plasmin leads to their degradation
-
-
?
additional information
?
-
-
plasminogen activator plays a pivotal role in internalisation of bacteria by HeLa cells. Intracellular signalling and cytoskeletal rearrangement is involved in Yersinia pestis plasminogen activator mediated HeLa cell invasion
-
-
?
additional information
?
-
-
the invasion of alveolar macrophages by Yersinia pestis depends both in vitro and in vivo on the expression of plasminogen activator Pla. Macrophages and transfectants expressing C-type lectin receptor DEC-205, but not their negative counterparts, phagocytose plasminogen activator Pla-expressing Yersinia pestis and Escherichia coli K12 more efficiently than Pla-negative controls. The interactions between Pla-expressing bacteria and DEC-205-expressing transfectants or alveolar macrophages can be inhibited by an anti-DEC-205 antibody. The blockage of the Pla-DEC-205 interaction reduces the dissemination of Yersinia pestis in mice
-
-
?
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metabolism
plasminogen is an abundant circulating zymogen of the serine protease plasmin, which is the key enzyme in fibrinolysis. The physiological plasminogen activation by uPA (EC 3.4.21.73) or tPA (EC 3.4.21.68) is a single cut at the peptide bond R560-V561, which yields the two-chain active plasmin enzyme. Pla rapidly cleaves the same peptide as do the human physiological activators, and the formed plasmin remains enzymatically active as Pla does not degrade the B chain of plasmin that contains the protease catalytic domain
evolution
comparative analysis of the sequences of the pro-omptin Pla with other omptin family proteases, such as PgtE from Salmonella enterica (EC 3.4.23.49), SopA from Shigella flexneri, and OmpT and OmpP from Escherichia coli reveals the location of predicted linear B-cell epitopes in either identical positions or in a very close proximity to all nine Pla epitopes predicted from library, and identified serologically using human anti-Pla antisera, overview
evolution
the enzyme belongs to the omptin family of enzymes
evolution
the modern isoform of Pla (T259) with an increased protease activity is found in Yersinia pestis subsp. pestis strains that are highly virulent for humans. The pathogenicity factor is absent in representatives of the Yersinia pestis subsp. microtus bv. caucasica/SNP-type 0.PE2, while an ancestral Pla isoform (I259) with characteristics similar to the properties of omptins from less virulent enterobacteria is found in three representatives of Yersinia pestis subsp. microtus (SNP-types 0.PE3 and 0.PE4), which are, as a rule, avirulent to guinea pigs and humans. Distribution of Pla isoforms among natural isolates of Yersinia pestis of different origin, overview
evolution
the pathogenicity factor is absent in representatives of the Yersinia pestis subsp. microtus bv. caucasica/SNP-type 0.PE2, while an ancestral Pla isoform (I259) with characteristics similar to the properties of omptins from less virulent enterobacteria is found in three representatives of Yersinia pestis subsp. microtus (SNP-types 0.PE3 and 0.PE4), which are, as a rule, avirulent to guinea pigs and humans. The modern isoform of Pla (T259) with an increased protease activity is found in Yersinia pestis subsp. pestis strains that are highly virulent for humans. Sequencing of pla genes from 118 Yersinia pestis subsp. microtus isolates reveals the absence of this gene in the strains belonging to bv. caucasica. All remaining isolates of Yersinia pestis subsp. microtus contain the ancestral Pla isoform (I259). Distribution of Pla isoforms among natural isolates of Yersinia pestis of different origin, overview
evolution
-
the pathogenicity factor is absent in representatives of the Yersinia pestis subsp. microtus bv. caucasica/SNP-type 0.PE2, while an ancestral Pla isoform (I259) with characteristics similar to the properties of omptins from less virulent enterobacteria is found in three representatives of Yersinia pestis subsp. microtus (SNP-types 0.PE3 and 0.PE4), which are, as a rule, avirulent to guinea pigs and humans. The modern isoform of Pla (T259) with an increased protease activity is found in Yersinia pestis subsp. pestis strains that are highly virulent for humans. Sequencing of pla genes from 118 Yersinia pestis subsp. microtus isolates reveals the absence of this gene in the strains belonging to bv. caucasica. All remaining isolates of Yersinia pestis subsp. microtus contain the ancestral Pla isoform (I259). Distribution of Pla isoforms among natural isolates of Yersinia pestis of different origin, overview
-
evolution
-
comparative analysis of the sequences of the pro-omptin Pla with other omptin family proteases, such as PgtE from Salmonella enterica (EC 3.4.23.49), SopA from Shigella flexneri, and OmpT and OmpP from Escherichia coli reveals the location of predicted linear B-cell epitopes in either identical positions or in a very close proximity to all nine Pla epitopes predicted from library, and identified serologically using human anti-Pla antisera, overview
-
malfunction
-
eliminating Pla expression in a fully virulent Yersinia pestis strain decreases its LD50 by 6 orders of magnitude in a mouse model of bubonic plague
malfunction
-
Pla deficient Yersinia pestis disseminate to regional lymph nodes after subcutaneous inoculation but do not cause the lymphadenopathy observed with wild-type Yersinia pestis infections
malfunction
-
survival of mice infected with Pla-deficient Yersinia pestis is greater than cohorts infected with wild-type Yersinia Pestis. Survival advantage is negated, if fibrinogen knockout mice are infected instead, directly implicating the host coagulation system as a target for Pla's role in virulence
malfunction
deletion of Pla results in a decreased Yersinia pestis bacterial burden in the host lung and failure to progress into the lethal proinflammatory phase of disease. Deletion of Pla does not alter adherence to and/or secretion into THP-1 cells. Infection of human precision-cut lung slices (hPCLS) with the knockout DELTApla strain results in significantly reduced Yersinia outer protein (Yop) translocation early after infection and continuing to 4 hours-post-infection. And deletion of Pla results in decreased Yersinia pestis T3S into alveolar macrophages in vivo during pneumonic plague. Addition of Pla to Yersinia pestis lacking all five known adhesins partially restores adherence and Yop delivery to macrophages derived from the human monocytic cell line THP-1 and human epithelial type 2 (HEp-2) cells, suggesting that Pla may contribute to adherence and Yop translocation in vitro
malfunction
introducing the single point mutation D206A into the active site of Pla suffices to render fully virulent Yersinia pestis susceptible to primed T-cells
malfunction
-
introducing the single point mutation D206A into the active site of Pla suffices to render fully virulent Yersinia pestis susceptible to primed T-cells
-
physiological function
-
1. Pla expression results in attenuated inflammatory cell recruitment (particularly neutrophils) to infected lesions 2. Pla expression causes a structural derangement of infected lymph tissue characterized by lymphadenitis, necrosis, hemorrhage, thrombosis, and disorganized masses of infiltrating bacteria. 3. Pla expression promotes the systemic dissemination of the infection
physiological function
-
Pla works to accelerate the initiation phase of blood clotting by activating the first enzyme in blood clotting (factor VIIa) and inactivating its most important protease inhibitor in plasma (TFPI). This is highly reminiscent of the ability of Pla to activate plasminogen to plasmin and to inactivate its plasma inhibitor, alpha2-antiplasmin
physiological function
-
the outer membrane plasminogen activator Pla of Yersinia pestis is a central virulence factor in plague
physiological function
-
Yersinia pestis binding to fibronectin is mediated through Ail protein and plasminogen activator Pla
physiological function
cleavage of Yersinia pestis autotransporter YapE by protease Pla is required to mediate bacterial aggregation and adherence to eukaryotic cells. Post-translation modification of YapE appears to be specific to Yersinia pestis. It was acquired along with the acquisition ofplasmid pPCP1 during the divergence of Yersinia pestis from Yersinia pseudotuberculosis, and is the first evidence of a mechanism to regulate bacterial adherence
physiological function
-
the plasminogen activator Pla single and the Braun lipoprotein Lpp Pla double mutant are unable to survive efficiently in murine and human macrophages. The levels of Pla and its associated protease activity are not affected in the Lpp single mutant, and, likewise, deletion of the Pla gene from wild-type does not alter Lpp levels. The ability of the Lpp Pla double mutant to be phagocytized by macrophages, to stimulate production of tumor necrosis factor-alpha and interleukin-6, and to activate the nitric oxide killing pathways of the host cells remains unaltered when compared to the wild-type-infected macrophages. Macrophages infected with either the wild-type or the Lpp Pla double mutant are equally efficient in their uptake of zymosan particles
physiological function
Pla of the enteropathogen Yersinia pestis is a surface-exposed, transmembrane beta-barrel proteases of the omptin family that exhibit a complex array of interactions with the hemostatic systems in vitro, the protease is an established virulence factor. Pla favors fibrinolysis by direct activation of plasminogen, inactivation of the serpins plasminogen activator inhibitor-1 and alpha2-antiplasmin, inactivation of the thrombin-activable fibrinolysis inhibitor, and activation of single-chain urokinase. Inactivation of alpha2AP enables proteolysis by the Pla-generated plasmin. The enzymatic activity of the protease is strongly influenced by the environment-induced variations in lipopolysaccharide that binds to the beta-barrel. The protease cleaves the tissue factor pathway inhibitor and thus also expresses procoagulant activity. Some of the functions observed for Pla, such as adhesiveness to laminin and invasiveness into human cells as well as efficient plasmin generation are not shown by PgtE (EC 3.4.23.49) or OmpT. Pla is adapted to support efficient plasminogen activation in the bubonic plague and to enhance bacterial survival in the lungs
physiological function
-
plasminogen activator inhibitor-1 (PAI-1) is an in vivo target of the Pla protease in the lungs during pneumonic plague. PAI-1 is a key regulator of the pulmonary innate immune response and contributes to the regulation of cytokine production and promotion of neutrophil recruitment during Yerisnia pestis respiratory infection. The inactivation of PAI-1 by Yersinia pestis alters the host environment to promote virulence. PAI-1 restricts the proliferation of Yersinia pestis in the absence of enzyme Pla
physiological function
the activity of the plasminogen activator protease Pla is the key to the progression of infection of Yersinia pestis in humans. Enzyme Pla facilitates type 3 secretion into primary alveolar macrophages but not into the commonly used THP-1 cell line. Analysis of the role of Pla in promoting optimal type 3 secretion using primary human tissue with relevant host cell heterogeneity in human precision-cut lung slices, a model of living tissue. Pla is a key player in the early host/pathogen interactions and a key virulence factor. Pla plays a role in adherence to alveolar macrophages that may not be detected using immortalized cell lines
physiological function
the plasminogen activator Pla is a protease that promotes fibrin degradation and prevents T cell-mediated defense against fully virulent Yersinia pestis. Pla functions to thwart fibrin-dependent T-cell-mediated defense against plague by promoting fibrinolysis. The presence of primed CD8 T-cells can suffice to protect against a lethal dose (LD) of a virulent Yersinia pestis strain rendered deficient in Pla activity in a fibrin-dependent manner
physiological function
-
the plasminogen activator Pla is a protease that promotes fibrin degradation and prevents T cell-mediated defense against fully virulent Yersinia pestis. Pla functions to thwart fibrin-dependent T-cell-mediated defense against plague by promoting fibrinolysis. The presence of primed CD8 T-cells can suffice to protect against a lethal dose (LD) of a virulent Yersinia pestis strain rendered deficient in Pla activity in a fibrin-dependent manner
-
physiological function
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plasminogen activator inhibitor-1 (PAI-1) is an in vivo target of the Pla protease in the lungs during pneumonic plague. PAI-1 is a key regulator of the pulmonary innate immune response and contributes to the regulation of cytokine production and promotion of neutrophil recruitment during Yerisnia pestis respiratory infection. The inactivation of PAI-1 by Yersinia pestis alters the host environment to promote virulence. PAI-1 restricts the proliferation of Yersinia pestis in the absence of enzyme Pla
-
additional information
the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Yersinia pestis propagation in the host. Analysis of intraspecies distribution, intrinsic disorder propensity, and contribution to virulence of the two isoforms of Yersinia pestis plasminogen activator Pla, overview. Survival curves of the endemic I259 Pla+ strains are similar to the parent Pla-negative variants, but significant difference in mean time to death post infection between the Pla- strains and their I259 Pla+ variants can be seen only in the isogenic set of Yersinia pestis subsp. pestis strains. An essential role for the outer membrane protease Pla evolution in Yersinia pestis bubonic infection exacerbation is suggested that is necessary for intensification of epidemic process from endemic natural focality with sporadic cases in humans to rapidly expanding epizootics followed by human epidemic outbreaks, local epidemics or even pandemics. Pla expression is associated with a marked ability to colonize the viscera and thus cause lethal infection upon administration by peripheral routes of infection, such as intradermal or subcutaneous. The Pla activity is not required to initiate lethal disease by intravenous injection, which provides immediate access to fixed macrophages lining the capillary beds of the liver and spleen. Virulence study of Yersinia pestis expressing different isoforms of Pla in a bubonic plague model
additional information
the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Yersinia pestis propagation in the host. Analysis of intraspecies distribution, intrinsic disorder propensity, and contribution to virulence of the two isoforms of Yersinia pestis plasminogen activator Pla, overview. Survival curves of the endemic I259 Pla+ strains are similar to the parent Pla-negative variants, but significant difference in mean time to death post infection between the Pla- strains and their I259 Pla+ variants can be seen only in the isogenic set of Yersinia pestis subsp. pestis strains. Pla expression is associated with a marked ability to colonize the viscera and thus cause lethal infection upon administration by peripheral routes of infection, such as intradermal or subcutaneous. The Pla activity is not required to initiate lethal disease by intravenous injection, which provides immediate access to fixed macrophages lining the capillary beds of the liver and spleen. Virulence study of Yersinia pestis expressing different isoforms of Pla in a bubonic plague model
additional information
-
the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Yersinia pestis propagation in the host. Analysis of intraspecies distribution, intrinsic disorder propensity, and contribution to virulence of the two isoforms of Yersinia pestis plasminogen activator Pla, overview. Survival curves of the endemic I259 Pla+ strains are similar to the parent Pla-negative variants, but significant difference in mean time to death post infection between the Pla- strains and their I259 Pla+ variants can be seen only in the isogenic set of Yersinia pestis subsp. pestis strains. An essential role for the outer membrane protease Pla evolution in Yersinia pestis bubonic infection exacerbation is suggested that is necessary for intensification of epidemic process from endemic natural focality with sporadic cases in humans to rapidly expanding epizootics followed by human epidemic outbreaks, local epidemics or even pandemics. Pla expression is associated with a marked ability to colonize the viscera and thus cause lethal infection upon administration by peripheral routes of infection, such as intradermal or subcutaneous. The Pla activity is not required to initiate lethal disease by intravenous injection, which provides immediate access to fixed macrophages lining the capillary beds of the liver and spleen. Virulence study of Yersinia pestis expressing different isoforms of Pla in a bubonic plague model
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D212R
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111% of wild-type plasminogen activation
D84A
-
3.7% of wild-type plasminogen activation
D97A
-
56% of wild-type plasminogen activation
E217S
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52% of wild-type plasminogen activation
F215Y
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42% of wild-type plasminogen activation
G178A/L179A
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mutation decreases laminin binding in the YPYIPTL region
H101V
-
0.8% of wild-type plasminogen activation
H108V
-
121% of wild-type plasminogen activation
H203V
-
109% of wild-type plasminogen activation
H208V
-
1.7% of wild-type plasminogen activation
H28V
-
125% of wild-type plasminogen activation
H98V
-
94% of wild-type plasminogen activation
K218A
-
103% of wild-type plasminogen activation
K240A
-
151% of wild-type plasminogen activation
K249A
-
132% of wild-type plasminogen activation
K254A
-
90% of wild-type plasminogen activation
K262A
-
85% of wild-type plasminogen activation
K280A
-
98% of wild-type plasminogen activation
L213I
-
123% of wild-type plasminogen activation
L65A/T66A/L67A
-
mutation decreases laminin binding in the WSLLTPA region
M210G
-
58% of wild-type plasminogen activation
R211K
-
11% of wild-type plasminogen activation
S267A
-
108% of wild-type plasminogen activation
S77A
-
133% of wild-type plasminogen activation
T259I
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the substitution impairs fibrinolytic activity and plasminogen activation
D206A
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site-directed mutagenesis, introducing the single point mutation into the active site of Pla suffices to render fully virulent Yersinia pestis susceptible to primed T-cells. The protective capacity of YopE-specific CD8 T cells against CO92 Pla-D206A is abrogated in mice with low levels of tissue factor activity as well as in PAI-1/TAFI double knockout mice. In addition, YopE-specific CD8 T cells poorly protect wild-type mice treated with Coumadin, a pharmacologic anticoagulant that reduces production of fibrin
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D206A
-
proteolytic activity is abolished
D206A
-
1.3% of wild-type plasminogen activation
D206A
site-directed mutagenesis, introducing the single point mutation into the active site of Pla suffices to render fully virulent Yersinia pestis susceptible to primed T-cells. The protective capacity of YopE-specific CD8 T cells against CO92 Pla-D206A is abrogated in mice with low levels of tissue factor activity as well as in PAI-1/TAFI double knockout mice. In addition, YopE-specific CD8 T cells poorly protect wild-type mice treated with Coumadin, a pharmacologic anticoagulant that reduces production of fibrin
D86A
-
3.5% of wild-type plasminogen activation
D86A
inactive, crystallization data
S99A
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proteolytic activity is abolished
S99A
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1% of wild-type plasminogen activation
additional information
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the acyltransferase gene mutant lpxM has an altered activity of plasminogen activator Pla
additional information
swapping of ten amino acid residues at two surface loops of Pla and membrane protease Epo of the plant pathogenic Erwinia pyrifoliae introduces plasminogen activation capacity in Epo and inactivates the function in Pla
additional information
the Pla I259T modification is not required to cause pneumonic plague in the murine intranasal model
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