Stability of the Octameric Structure Affects Plasminogen-Binding Capacity of Streptococcal Enolase

Cork, Amanda J.; Ericsson, Daniel; Law, Ruby H. P.; Casey, Lachlan W.; Valkov, Eugene; Bertozzi, Carlo; Stamp, Anna; Jovcevski, Blagojce; Aquilina, J. Andrew; Whisstock, James C.; Walker, Mark J.; Kobe, Boštjan

doi:10.1371/journal.pone.0121764

Cited by 16 publications

(42 citation statements)

References 64 publications

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“…A structure model of SEN based on the crystal structure of GAS and S. pneumoniae α-enolase indicates that SEN forms an octameric structure comprising a tetramer of dimer 22 36 37 . These models show that lysine residues of SEN at positions 252 and 255 within a unique lysine-rich PLG-binding motif are located in a surface-exposed loop at the edge of the toroidal octameric protein.…”

Section: Discussionmentioning

confidence: 99%

“…Internal lysine residues in the closely related α-enolase of S. pneumoniae have also been reported to play crucial roles not only in the acquisition of PLG, but also in their virulence in a mouse infection model 38 . Recent structural and biophysical analyses of GAS SEN demonstrated that mutations in the minor inter-subunit interface induce destabilization of the octameric structure, thereby promoting the accessibility of PLG to its binding sites 37 . Since C-terminus lysine residues are located in the minor interface, we speculated that mutations in this region cause a conformational change of SEN, which might facilitate interaction of PLG with internal PLG-binding sites.…”

Section: Discussionmentioning

confidence: 99%

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Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

Sumitomo

Nakata

Higashino

et al. 2016

Sci Rep

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Group A Streptococcus (GAS) is a human-specific pathogen responsible for local suppurative and life-threatening invasive systemic diseases. Interaction of GAS with human plasminogen (PLG) is a salient characteristic for promoting their systemic dissemination. In the present study, a serotype M28 strain was found predominantly localized in tricellular tight junctions of epithelial cells cultured in the presence of PLG. Several lines of evidence indicated that interaction of PLG with tricellulin, a major component of tricellular tight junctions, is crucial for bacterial localization. A site-directed mutagenesis approach revealed that lysine residues at positions 217 and 252 within the extracellular loop of tricellulin play important roles in PLG-binding activity. Additionally, we demonstrated that PLG functions as a molecular bridge between tricellulin and streptococcal surface enolase (SEN). The wild type strain efficiently translocated across the epithelial monolayer, accompanied by cleavage of transmembrane junctional proteins. In contrast, amino acid substitutions in the PLG-binding motif of SEN markedly compromised those activities. Notably, the interaction of PLG with SEN was dependent on PLG species specificity, which influenced the efficiency of bacterial penetration. Our findings provide insight into the mechanism by which GAS exploits host PLG for acceleration of bacterial invasion into deeper tissues via tricellular tight junctions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

Sumitomo

Nakata

Higashino

et al. 2016

Sci Rep

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“…The X-ray crystal structure of Str enolase has recently been deposited in the data bank (3ZLH.PDB Fig 1 ). The coordinates were kindly given to us by the authors (Cork, Ericsson, Law, Casey, Valkov, Bertozzi, Stamp, Aquilina, Whisstock, Walker and Kobe) [ 22 ]. This protein contains one mutation (E77K) relative to the Str enolase DB.…”

Section: Resultsmentioning

confidence: 99%

“…There has been a significant amount of work done on mutant forms of enolase from Streptococcus pyogenes and Streptococcus pneumoniae [ 7 , 8 , 22 , 33 – 35 ]. Cork et al [ 22 ] recently found that changing K362 to alanine destabilizes the Str enolase. Much of the rest of the above cited work was aimed at determining the role of specific residues, especially residues 434 and 435, in the binding of plasminogen.…”

Section: Discussionmentioning

confidence: 99%

The Energetics of Streptococcal Enolase Octamer Formation: The Quantitative Contributions of the Last Eight Amino Acids at the Carboxy-Terminus

2015

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The enolase produced by Streptococcus pyogenes is a homo-octamer whose overall shape resembles that of a donut. The octamer is best described as a tetramer of dimers. As such, it contains two types of interfaces. The first is common to almost all enolases as most enolases that have been studied are dimers. The second is unique to the octamers and includes residues near the carboxy-terminus. The primary sequence of the enolase contains 435 residues with an added 19 as an N-terminal hexahistine tag. We have systematically truncated the carboxy-terminus, individually removing the first 8 residues. This gave rise to a series of eight structures containing respectively, 435, 434, 433, 432, 431, 430, 429 and 427 residues. The truncations cause the protein to gradually dissociate from octamers to enzymatically inactive monomers with very small amounts of intermediate tetramers and dimers. We have evaluated the contributions of the missing residues to the monomer/octamer equilibrium using a combination of analytical ultracentrifugation and activity assays. For the dissociation reaction, truncation of all eight C-terminal residues resulted in a diminution in the standard Gibbs energy of dissociation of about 59 kJ/mole of octamer relative to the full length protein. Considering that this change is spread over eight subunits, this translates to a change in standard Gibbs interaction energy of less than 8 kJ/mole of monomer distributed over the eight monomers. The resulting proteins, containing 434, 433, 432, 431, 430, 429 and 427 residues per monomer, showed intermediate free energies of dissociation. Finally, three other mutations were introduced into our reference protein to establish how they influenced the equilibrium. The main importance of this work is it shows that for homo-multimeric proteins a small change in the standard Gibbs interaction energy between subunits can have major physiological effects.

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“…Interaction with KR1 and KR5 domains of Plg occurs through lysine residues located at the C-terminal end of enolase, as well as on another internal binding site. Plg undergoes a conformational change to expose the cut site for PAs in order to induce Plm formation [ 144 ].…”

Section: Plg–enolase Interactionmentioning

confidence: 99%

Plasminogen-binding proteins as an evasion mechanism of the host’s innate immunity in infectious diseases

et al. 2018

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Pathogens have developed particular strategies to infect and invade their hosts. Amongst these strategies’ figures the modulation of several components of the innate immune system participating in early host defenses, such as the coagulation and complement cascades, as well as the fibrinolytic system. The components of the coagulation cascade and the fibrinolytic system have been proposed to be interfered during host invasion and tissue migration of bacteria, fungi, protozoa, and more recently, helminths. One of the components that has been proposed to facilitate pathogen migration is plasminogen (Plg), a protein found in the host’s plasma, which is activated into plasmin (Plm), a serine protease that degrades fibrin networks and promotes degradation of extracellular matrix (ECM), aiding maintenance of homeostasis. However, pathogens possess Plg-binding proteins that can activate it, therefore taking advantage of the fibrin degradation to facilitate establishment in their hosts. Emergence of Plg-binding proteins appears to have occurred in diverse infectious agents along evolutionary history of host–pathogen relationships. The goal of the present review is to list, summarize, and analyze different examples of Plg-binding proteins used by infectious agents to invade and establish in their hosts. Emphasis was placed on mechanisms used by helminth parasites, particularly taeniid cestodes, where enolase has been identified as a major Plg-binding and activating protein. A new picture is starting to arise about how this glycolytic enzyme could acquire an entirely new role as modulator of the innate immune system in the context of the host–parasite relationship.

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Stability of the Octameric Structure Affects Plasminogen-Binding Capacity of Streptococcal Enolase

Cited by 16 publications

References 64 publications

Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

The Energetics of Streptococcal Enolase Octamer Formation: The Quantitative Contributions of the Last Eight Amino Acids at the Carboxy-Terminus

Plasminogen-binding proteins as an evasion mechanism of the host’s innate immunity in infectious diseases

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