The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment
Annually, over 18 million disease cases and half a million deaths worldwide are estimated to be caused by Group A Streptococcus. ScpA (or C5a peptidase) is a well characterised member of the cell enveleope protease family, which possess a S8 subtilisin-like catalytic domain and a shared multi-domain architecture. ScpA cleaves complement factors C5a and C3a, impairing the function of these critical anaphylatoxins and disrupts complement-mediated innate immunity. Although the high resolution structure of ScpA is known, the details of how it recognises its substrate are only just emerging. Previous studies have identified a distant exosite on the 2nd fibronectin domain that plays an important role in recruitment via an interaction with the substrate core. Here, using a combination of solution NMR spectroscopy, mutagenesis with functional assays and computational approaches we identify a second exosite within the protease-associated (PA) domain. We propose a model in which the PA domain assists optimal delivery of the substrate’s C terminus to the active site for cleavage.
Understanding and exploiting Group A streptococcal anti-chemotactic proteases in vaccines for infection
Wellcome TrustFind out more...
Synthesis and Solid State Pharmaceutical Centre (SSPC)
Science Foundation IrelandFind out more...
PublicationBBA - Proteins and Proteomics, 2023 1871, 140946
Other Funding informationThis work was supported by the Wellcome Trust Collaborative Award 215539: ‘Understanding and exploiting Group A streptococcal anti-chemotactic proteases in vaccines for infection’ to SS, SM and JEP; Science Foundation Ireland grant numbers 21/FFP-P/10109 and 12/ RC/2275 to JC and TK. SS acknowledges support of the NIHR Imperial Biomedical Research Centre.
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