title: The crystal structure of the streptococcal collagen-like protein 2 globular domain from invasive M3-type group A Streptococcus shows significant similarity to immunomodulatory HIV protein gp41.
abstract: The arsenal of virulence factors deployed by streptococci includes streptococcal collagen-like (Scl) proteins. These proteins, which are characterized by a globular domain 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 observed 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 interdomain motions that 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.
authors.affiliation: From the Institute of Biostructures and Bioimaging, Consiglio Nazionale delle Ricerche, Via Mezzocannone 16, I-80134 Napoli, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Squeglia
authors.forename: Beth
authors.initials: B
authors.lastname: Bachert
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Slawomir
authors.initials: S
authors.lastname: Lukomski
authors.forename: Rita
authors.initials: R
authors.lastname: Berisio
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012996:Solutions; D013297:Streptococcus pyogenes / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D001426:Bacterial Proteins; D015700:HIV Envelope Protein gp41; D007155:Immunologic Factors; D012996:Solutions; D003094:Collagen
keywords: Collagen; Crystal Structure; Molecular Dynamics; Protein Folding; Streptococcus