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Cited by 50Enzyme Structure and FunctionBiochemical and Structural CharacterizationComplement system in diseases

Model for Substrate Interactions in C5a Peptidase from Streptococcus pyogenes: a 1.9 Å Crystal Structure of the Active Form of ScpA.

Kagawa, Todd F., O'Connell, Maurice R., Mouat, Pania, Paoli, Max, O'Toole, Paul W., Cooney, Jakki C.·2009·Journal of Molecular Biology
DOI 10.1016/j.jmb.2008.12.074
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Abstract

The crystal structure of an active form of ScpA has been solved to 1.9 A resolution. ScpA is a multidomain cell-envelope subtilase from Streptococcus pyogenes that cleaves complement component C5a. The catalytic triad of ScpA is geometrically consistent with other subtilases, clearly demonstrating that the additional activation mechanism proposed for the Streptococcus agalactiae homologue (ScpB) is not required for ScpA. The ScpA structure revealed that access to the catalytic site is restricted by variable regions in the catalytic domain (vr7, vr9, and vr11) and by the presence of the inserted protease-associated (PA) domain and the second fibronectin type III domains (Fn2). Modeling of the ScpA-C5a complex indicates that the substrate binds with carboxyl-terminal residues (65-74) extended through the active site and core residues (1-64) forming exosite-type interactions with the Fn2 domain. This is reminiscent of the two-site mechanism proposed for C5a binding to its receptor. In the nonprime region of the active site, interactions with the substrate backbone are predicted to be more similar to those observed in kexins, involving a single beta-strand in the peptidase. However, in contrast to kexins, there would be diminished emphasis on side-chain interactions, with little charged character in the S3-S1 and S6-S4 subsites occupied by the side chains of residues in vr7 and vr9. Substrate binding is anticipated to be dominated by ionic interactions in two distinct regions of ScpA. On the prime side of the active site, salt bridges are predicted between P1', P2', and P7' residues, and residues in the catalytic and PA domains. Remote to the active site, a larger number of ionic interactions between residues in the C5a core and the Fn2 domain are observed in the model. Thus, both PA and Fn2 domains are expected to play significant roles in substrate recognition.

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Crossref · 10.1016/j.jmb.2008.12.074

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  • The structure determined by Kagawa et al. (2009) was determined on a recombinant protein produced in E. coli containing the pro-peptide and only omitting the signal peptide; no substitutions were made and the protein had enzymatic activity.

    “The structure determined by Kagawa et al. (2009) was determined on a recombinant protein produced in E. coli containing the pro-peptide and only omitting the signal peptide. No substitutions were made and the protein had enzymatic activity (Kagawa et al., 2009).”

    From Modeled Structure of the Cell Envelope Proteinase of Lactococcus lactis (2020) · cites this paper as Kagawa et al., 2009

  • Kagawa et al. (2009) modeled the interaction between the C5a protease and the C5a peptide and concluded that the specificity arises from complementarity between the surface of the Fn2 domain and the core structure of the peptide.

    “Kagawa et al. (2009) modeled the interaction between the C5a protease and the C5a peptide and concluded that the specificity arises from complementarity between the surface of the Fn2 domain and the core structure of the peptide (Kagawa et al., 2009).”

    From Modeled Structure of the Cell Envelope Proteinase of Lactococcus lactis (2020) · cites this paper as Kagawa et al., 2009

  • Eighteen amino acids of C5a peptide between 1 and 64 could form hydrogen-, ionic-, and hydrophobic interactions with 24 amino acids on the proteinase in the region between residue 751-887; this region corresponds to residues 857-993 in MS22337 PrtP, including the "blue region" of Figure 5D.

    “Eighteen amino acids of C5a peptide between 1 and 64 could form hydrogen-, ionic-, and hydrophobic interactions with 24 amino acids on the proteinase in the region between residue 751–887 (Kagawa et al., 2009). This region would correspond to the region between residues 857–993 in MS22337 PrtP, and thus include “the blue region” of Figure 5D which also include the residues shown to determine the S”

    From Modeled Structure of the Cell Envelope Proteinase of Lactococcus lactis (2020) · cites this paper as Kagawa et al., 2009

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Authors
Kagawa, T. F., O'Connell, M. R., Mouat, P., Paoli, M., O'Toole, P. W., & Cooney, J. C.
Affiliations
  • University of Limerick (IE)
  • Massey University (NZ)
  • University of Nottingham (GB)
Corresponding author
  • Kagawa, Todd F.
  • Cooney, Jakki C.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2009-02
Volume
386
Issue
3
Pages
754-772
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2008.12.074
OpenAlex
W2018831165
Cited by
50
References
70
Citations by year
2026: 5 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 5
FWCI
1.45
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Royal Irish Academy
  • University of Limerick
  • Massey University
  • Irish Research Council for Science, Engineering and Technology
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
ScpA, C5a peptidase, Streptococcus pyogenes, subtilisin-like protease, substrate recognition, fibronectin type III domain, catalytic triad, variable region, salt bridges, ScpB
MeSH terms
Amino Acid Sequence, Models, Molecular, Molecular Sequence Data, Endopeptidases, Protein Binding, Streptococcus pyogenes, Complement C5a, Sequence Alignment, Protein Structure, Tertiary, Crystallography, X-Ray, Adhesins, Bacterial, Catalytic Domain, Protein Structure, Quaternary

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