TY - JOUR
T1 - The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment
AU - McKenna, Sophie
AU - Aylward, Frances
AU - Miliara, Xeni
AU - Lau, Rikin J.
AU - Huemer, Camilla Berg
AU - Giblin, Sean P.
AU - Huse, Kristin K.
AU - Liang, Mingyang
AU - Reeves, Lucy
AU - Pearson, Max
AU - Xu, Yingqi
AU - Rouse, Sarah L.
AU - Pease, James E.
AU - Sriskandan, Shiranee
AU - Kagawa, Todd F.
AU - Cooney, Jakki
AU - Matthews, Stephen
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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.
AB - 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.
KW - Bacterial cell envelope proteases
KW - C5a and C3a
KW - Group A Streptococcus
KW - ScpA
KW - Solution NMR
UR - http://www.scopus.com/inward/record.url?scp=85168161501&partnerID=8YFLogxK
U2 - 10.1016/j.bbapap.2023.140946
DO - 10.1016/j.bbapap.2023.140946
M3 - Article
C2 - 37562488
AN - SCOPUS:85168161501
SN - 1570-9639
VL - 1871
SP - 140946
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
IS - 6
M1 - 140946
ER -