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

Biochim Biophys Acta Proteins Proteom. 2023 Nov 1;1871(6):140946. doi: 10.1016/j.bbapap.2023.140946. Epub 2023 Aug 9.

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.

Keywords: Bacterial cell envelope proteases; C5a and C3a; Group A Streptococcus; ScpA; Solution NMR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Immunity, Innate
  • Peptide Hydrolases*
  • Streptococcus pyogenes*

Substances

  • Peptide Hydrolases