The group A streptococcal collagen-like protein 1, Scl1, mediates biofilm formation by targeting the EDA-containing variant of cellular fibronectin expressed in wounded tissue.
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, 26506, USA. Molecular Microbiology
(Impact Factor: 4.42).
12/2012; 87(3). DOI: 10.1111/mmi.12125
Wounds are known to serve as portals of entry for group A Streptococcus (GAS). Subsequent tissue colonization is mediated by interactions between GAS surface proteins and host extracellular matrix components. We recently reported that the streptococcal collagen-like protein-1, Scl1, selectively binds the cellular form of fibronectin (cFn) and also contributes to GAS biofilm formation on abiotic surfaces. One structural feature of cFn, which is predominantly expressed in response to tissue injury, is the presence of a spliced variant containing extra domain A (EDA/EIIIA). We now report that GAS biofilm formation is mediated by the Scl1 interaction with EDA-containing cFn. Recombinant Scl1 proteins that bound cFn also bound recombinant EDA within the C-C' loop region recognized by the α(9) β(1) integrin. The extracellular 2-D matrix derived from human dermal fibroblasts supports GAS adherence and biofilm formation. Altogether, this work identifies and characterizes a novel molecular mechanism by which GAS utilizes Scl1 to specifically target an extracellular matrix component that is predominantly expressed at the site of injury in order to secure host tissue colonization.
Available from: jbc.org
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ABSTRACT: The arsenal of virulence factors deployed by streptococci include streptococcal collagen-like (Scl) proteins. These proteins, which are characterized by a globular and a collagen-like domain, play key roles in host-adhesion, host immune defense evasion and biofilm formation. In this work, we demonstrate that the Scl2.3 protein is expressed on the surface of invasive M3-type strain MGAS315 of Streptococcus pyogenes. We report the crystal structure of Scl2.3 globular domain, the first of any Scl. This structure shows a novel fold among collagen trimerization domains, of either bacterial or human origin. Despite there being low sequence identity, we observe that Scl2.3 globular domain structurally resembles the gp41 subunit of the envelope glycoprotein from human immunodeficiency virus type 1, an essential subunit for viral fusion to human T cells. We combined crystallographic data with modeling and molecular dynamics techniques to gather information on the entire lollipop-like Scl2.3 structure. Molecular dynamics data evidence a high flexibility of Scl2.3, with remarkable inter-domain motions which are likely instrumental to the protein biological function in mediating adhesive or immune-modulatory functions in host-pathogen interactions. Altogether, our results provide molecular tools for the understanding of Scl-mediated streptococcal pathogenesis and important structural insights for the future design of small molecular inhibitors of streptococcal invasion.
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ABSTRACT: A large number of collagen-like proteins have been identified in bacteria during the past ten years, principally from analysis of genome databases. These bacterial collagens share the distinctive Gly-Xaa-Yaa repeating amino acid sequence of animal collagens which underlies their unique triple-helical structure. A number of the bacterial collagens have been expressed in E. coli, and they all adopt a triple-helix conformation. Unlike animal collagens, these bacterial proteins do not contain the post-translationally modified amino acid, hydroxyproline, which is known to stabilize the triple-helix structure and may promote self-assembly. Despite the absence of collagen hydroxylation, the triple-helix structures of the bacterial collagens studied exhibit a high thermal stability of 35 - 39 °C, close to that seen for mammalian collagens. These bacterial collagens are readily produced in large quantities by recombinant methods, either in the original amino acid sequence or in genetically manipulated sequences. This new family of recombinant, easy to modify collagens could provide a novel system for investigating structural and functional motifs in animal collagens and could also form the basis of new biomedical materials with designed structural properties and functions.
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ABSTRACT: Increasing disease caused by beta-haemolytic streptococci indicates the need for improved understanding of pathogenesis.
Streptococcus pyogenes, or group A Streptococcus (GAS), causes significant disease worldwide. The closely related Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as causing a similar disease spectrum. Whole-genome sequencing applied to the study of outbreaks may reveal factors that contribute to pathogenesis and changes in epidemiology. The role of quorum sensing in biofilm formation, and interspecies communication with other streptococci, is discussed. GAS has evolved multiple mechanisms to evade the humoral arm of innate immunity, including complement, which is well known in protecting the host from bacteria, and the coagulation-fibrinolytic system, which is increasingly recognized as an innate immune effector.
Molecular biology has enhanced our understanding of the intricate balance of host-pathogen interactions that result in clearance or establishment of invasive streptococcal infection. Although the skin and oropharynx remain the usual ecological niche of GAS and SDSE, occasionally the bacteria find themselves within deeper tissues and blood. Recent research has armed us with better knowledge of bacterial adaptations to this alternative environment. However, the challenge is to translate this knowledge into clinical practice, through the development of novel therapeutic options and ultimately a vaccine against GAS.
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