Group A Streptococcus (GAS; Streptococcus pyogenes) causes a wide range of infections, including pharyngitis, impetigo, and necrotizing fasciitis, and results in over half a million deaths annually. GAS ScpC (SpyCEP), a 180-kDa surface-exposed, subtilisin-like serine protease, acts as an essential virulence factor that helps S. pyogenes evade the innate immune response by cleaving and inactivating C-X-C chemokines. ScpC is thus a key candidate for the development of a vaccine against GAS and other pathogenic streptococcal species. Here, we report the crystal structures of full-length ScpC wild-type, the inactive mutant, and the ScpC–AEBSF inhibitor complex. We show ScpC to be a multi-domain, modular protein consisting of nine structural domains, of which the first five constitute the PR + A region required for catalytic activity. The four unique C-terminal domains of this protein are similar to collagen-binding and pilin proteins, suggesting an additional role for ScpC as an adhesin that might mediate the attachment of S. pyogenes to various host tissues. The Cat domain of ScpC is similar to subtilisin-like proteases with significant difference to dictate its specificity toward C-X-C chemokines. We further show that ScpC does not undergo structural rearrangement upon maturation. In the ScpC–inhibitor complex, the bound inhibitor breaks the hydrogen bond between active-site residues, which is essential for catalysis. Guided by our structure, we designed various epitopes and raised antibodies capable of neutralizing ScpC activity. Collectively, our results demonstrate the structure, maturation process, inhibition, and substrate recognition of GAS ScpC, and reveal the presence of functional domains at the C-terminal region.
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In this issue of the Biochemical Journal, Tong et al. report how a sesquiterpene synthase generates eudesmane-type sesquiterpene diols in Tripterygium wilfordii and which residues are important for cyclization. The cover image shows the flower of T. wilfordii and the structure of cryptomeridiol synthase. The background depicts ancient Chinese text that recorded the medicinal benefits of T. wilfordii and the engineered manipulation in yeast to enhance the production of the eudesmane diol cryptomeridiol. For further details, see pages 2713–2725. Image kindly provided by Wei Gao (Capital Medical University, Beijing).
Structure of ScpC, a virulence protease from Streptococcus pyogenes, reveals the functional domains and maturation mechanism
Chacko Jobichen, Ying Chong Tan, Mahalakshmi Tirumuru Prabhakar, Digant Nayak, Debabrata Biswas, Navraj S. Pannu, Emanuel Hanski, J. Sivaraman; Structure of ScpC, a virulence protease from Streptococcus pyogenes, reveals the functional domains and maturation mechanism. Biochem J 14 September 2018; 475 (17): 2847–2860. doi: https://doi.org/10.1042/BCJ20180145
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