Structure of the Mature Streptococcal Cysteine Protease Exotoxin mSpeB in Its Active Dimeric Form

Olsen, Johan G.; Dagil, Robert; Niclasen, Louise Meinert; Sørensen, Ole E.; Kragelund, Birthe B.

doi:10.1016/j.jmb.2009.08.046

Cited by 18 publications

(26 citation statements)

References 29 publications

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“…Furthermore, there is evidence that the fl exible carboxy-terminal domain is important for the broad substrate specifi city and the active form of SpeBm is actually a dimer (Kagawa et al , 2000 ;Olsen et al , 2009 ;Wang et al , 2009 ). To protect itself from intracellular SpeB activity, S. pyogenes cotranscribes a cognate inhibitor, Spi, which is a structural homologue to the SpeB propeptide (Kagawa et al , 2005 ).…”

Section: Biochemical Properties Substrate Specifi City and Structurmentioning

confidence: 99%

Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins

Nelson¹,

Garbe

Collin

2011

BCHM

144

111

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Group A streptococcus ( Streptococcus pyogenes ) is an exclusively human pathogen that causes a wide spectrum of diseases ranging from pharyngitis, to impetigo, to toxic shock, to necrotizing fasciitis. The diversity of these disease states necessitates that S. pyogenes possess the ability to modulate both the innate and adaptive immune responses. SpeB, a cysteine proteinase, is the predominant secreted protein from S. pyogenes . Because of its relatively indiscriminant specifi city, this enzyme has been shown to degrade the extracellular matrix, cytokines, chemokines, complement components, immunoglobulins, and serum protease inhibitors, to name but a few of the known substrates. Additionally, SpeB regulates other streptococcal proteins by degrading them or releasing them from the bacterial surface. Despite the wealth of literature on putative SpeB functions, there remains much controversy about this enzyme because many of reported activities would produce contradictory physiological results. Here we review all known host and bacterial protein substrates for SpeB, their cleavage sites, and discuss the role of this enzyme in streptococcal pathogenesis based on the current literature.

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Section: Biochemical Properties Substrate Specifi City and Structurmentioning

confidence: 99%

Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins

Nelson¹,

Garbe

Collin

2011

BCHM

144

111

View full text Add to dashboard Cite

show abstract

“…1A). The apo-SpeB structure was determined by molecular replacement using the mature SpeB structure (Protein Data Bank entry 2UZJ) (21) as the initial search model. The final R cryst and R free values for the apo structure were 14.4 and 16.0%, respectively, with 97.6% of the residues in the most favored region of the Ramachandran plot ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Structure Solution and Refinement-The apo-SpeB structure was determined by molecular replacement with Phaser (25,26), using the previously published mature SpeB structure (2UZJ) (21) as the initial search model. The apo-SpeB structure then served as the search model for the E64 and Ac-AEIK-CHO SpeB complex structures.…”

Section: Methodsmentioning

confidence: 99%

Ultrahigh and High Resolution Structures and Mutational Analysis of Monomeric Streptococcus pyogenes SpeB Reveal a Functional Role for the Glycine-rich C-terminal Loop

González-Páez

Wolan

2012

Journal of Biological Chemistry

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Background: SpeB is a protease secreted from the pathogenic bacterium Streptococcus pyogenes. Results: Apo and inhibitor complex structures of SpeB reveal conformational changes associated with activation and binding. Conclusion:The glycine-rich C-terminal active site loop is required for substrate recognition and product release. Significance: Crystal structures and mutagenesis afford insights into the specificity of SpeB and the functional role of the active site loops in binding biological substrates.

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“…Structural bioinformatics tools allowed us to investigate mechanisms by which zinc could mediate its inhibitory effects on SpeB, which, as a widely studied GAS virulence factor, has been crystallized by several groups who aimed to identify the enzyme's catalytic residues, substrate-binding site, protein folding, and maturation process (38)(39)(40)(41). In all those cases, SpeB was crystallized either in its mature form or in the inactive zymogen form generated by replacing the active cysteine residue with serine.…”

Section: Discussionmentioning

confidence: 99%

“…In all those cases, SpeB was crystallized either in its mature form or in the inactive zymogen form generated by replacing the active cysteine residue with serine. Using the crystal structure of the mature form of SpeB (2UZJ), which was determined by Olsen et al (38), we were able to predict metalbinding sites in SpeB. As illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications

et al. 2014

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dStreptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin-and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal-binding sites in SpeB, one of which involves the catalytic-dyad residues 47 Cys and 195 His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections.

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Structure of the Mature Streptococcal Cysteine Protease Exotoxin mSpeB in Its Active Dimeric Form

Cited by 18 publications

References 29 publications

Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins

Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins

Ultrahigh and High Resolution Structures and Mutational Analysis of Monomeric Streptococcus pyogenes SpeB Reveal a Functional Role for the Glycine-rich C-terminal Loop

Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications

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