{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:39:13Z","timestamp":1762101553953},"reference-count":48,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Streptococcal 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\n            <jats:sup>47<\/jats:sup>\n            Cys and\n            <jats:sup>195<\/jats:sup>\n            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.\n          <\/jats:p>","DOI":"10.1128\/iai.01770-14","type":"journal-article","created":{"date-parts":[[2014,5,6]],"date-time":"2014-05-06T03:34:01Z","timestamp":1399347241000},"page":"2992-3001","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications"],"prefix":"10.1128","volume":"82","author":[{"given":"Karthickeyan","family":"Chella Krishnan","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"name":"Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santhosh","family":"Mukundan","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio A.","family":"Landero Figueroa","sequence":"additional","affiliation":[{"name":"University of Cincinnati\/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph A.","family":"Caruso","sequence":"additional","affiliation":[{"name":"University of Cincinnati\/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malak","family":"Kotb","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"name":"Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA"},{"name":"Veterans Affairs Hospital, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/653116"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198707163170305"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1410.071660"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/14.1.2"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2648"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(90)92777-F"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.13.3.470-511.2000"},{"key":"e_1_3_3_9_2","first-page":"93","volume-title":"Emerging infections 1","author":"Low DE","year":"1998","unstructured":"LowDESchwartzBMcGeerA. 1998. 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