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Issue 23, 2017, Issue in Progress
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Experimental identification and computational characterization of a novel extracellular metalloproteinase produced by Clostridium sordellii

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Abstract

Clostridium sordellii is a lethal pathogen for both animals and humans. Severe capillary leakage, toxic shock syndrome, and an extreme leukemoid reaction (LR), are hallmark features of C. sordellii infections and contribute to its high mortality rate. Here we report the discovery of a previously unknown and uncharacterized metalloproteinase of C. sordellii (referred as Mcs1) that cleaves human vascular cell adhesion molecule (VCAM)-1 in vitro, an adhesion molecule critical to hematopoietic precursor retention and leukocyte diapedesis. We successfully identified the open reading frame encoding Mcs1 within the ATCC 9714 genome and developed an Δmcs1 mutant strain using the ClosTron mutagenesis technology. No VCAM-1 proteolysis was observed from exotoxins collected from mutant strain cultures. Using advanced protein structural modeling and molecular dynamics simulation techniques, the 3D molecular structure and conformational features of Mcs1 were also characterized. Our data demonstrates that Mcs1 proteolytic activity is controlled by the electrostatic interactions between Glu113 and Arg227 residues and the gating motions within its cleft region. This pilot interdisciplinary investigation provided crucial experimental evidence of the existence of Mcs1 in C. sordellii and molecular insights into its 3D structure and proteolytic activity. These findings have the potential to help advance new therapeutics and diagnostics against deadly C. sordellii infections. Follow-up in vitro and in vivo work is under way to further characterize Mcs1 enzymatic kinetics and its role in C. sordellii pathogenesis.

Graphical abstract: Experimental identification and computational characterization of a novel extracellular metalloproteinase produced by Clostridium sordellii

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Publication details

The article was received on 02 Dec 2016, accepted on 22 Feb 2017 and first published on 02 Mar 2017


Article type: Paper
DOI: 10.1039/C6RA27654G
Citation: RSC Adv., 2017,7, 13928-13938
  • Open access: Creative Commons BY-NC license
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    Experimental identification and computational characterization of a novel extracellular metalloproteinase produced by Clostridium sordellii

    M. J. Aldape, A. Tao, D. D. Heeney, E. R. McIndoo, John M. French and D. Xu, RSC Adv., 2017, 7, 13928
    DOI: 10.1039/C6RA27654G

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