The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment

Sophie McKenna, Frances Aylward, Xeni Miliara, Rikin J. Lau, Camilla Berg Huemer, Sean P. Giblin, Kristin K. Huse, Mingyang Liang, Lucy Reeves, Max Pearson, Yingqi Xu, Sarah L. Rouse, James E. Pease, Shiranee Sriskandan, Todd F. Kagawa, Jakki Cooney, Stephen Matthews

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number140946
Pages (from-to)140946
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1871
Issue number6
DOIs
Publication statusPublished - 1 Nov 2023

Keywords

  • Bacterial cell envelope proteases
  • C5a and C3a
  • Group A Streptococcus
  • ScpA
  • Solution NMR

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