Structural analysis of extracellular ATP-independent chaperones of streptococcal species and protein substrate interactions
Streptococcal species are a leading cause of lower respiratory infections that annually affect millions of people worldwide. During infection, streptococcal species secrete a medley of virulence factors that allow the bacteria to colonize and translocate to deeper tissues. In many gram-positive bacteria, virulence factors are secreted from the cytosol across the bacterial membrane in an unfolded state. The bacterial membrane-cell wall interface is exposed to the potentially harsh extracellular environment, making it difficult for native virulence factors to fold before being released into the host. ATP-independent PPIase-type chaperones, PrsA and SlrA, are thought to facilitate folding and stabilization of several unfolded proteins to promote the colonization and spread of streptococci. Here, we present crystal structures of the molecular chaperones of PrsA and SlrA homologs from streptococcal species. We provide evidence that the <i>Streptococcus pyogenes</i> SlrA homolog, PpiA, has PPIase activity and binds to cyclosporine A. In addition, we show that <i>Streptococcus pneumoniae</i> PrsA and SlrA directly interact and fold the cholesterol-dependent pore-forming toxin and critical virulence determinant, pneumolysin.
Authors
- Charles Agbavor
- Dominika Borek (ORCID: https://orcid.org/0000-0002-4321-6253)
- K.J.F. Satchell (ORCID: https://orcid.org/0000-0003-3274-7611)
- Laty A. Cahoon (ORCID: https://orcid.org/0000-0003-2061-319X)
- G. Minasov (ORCID: https://orcid.org/0000-0001-5460-3462)
- Z. Wawrzak (ORCID: https://orcid.org/0000-0002-0186-0964)
- W.F. Anderson (ORCID: https://orcid.org/0000-0003-4181-8127)
- Alexei V. Savchenko (ORCID: https://orcid.org/0000-0002-5256-9237)
- Zbyszek Otwinowski (ORCID: https://orcid.org/0000-0003-3640-8545)
- Nicole L. Inniss (ORCID: https://orcid.org/0000-0002-1510-7412)
- P.J. Stogios (ORCID: https://orcid.org/0000-0001-8663-1425)
- Madeline Torres
- Scott Latimer
- Ludmilla Shuvalova
Institutions
- Northwestern University (US)
- University of Calgary (CA)
- University of Pittsburgh (US)
- University of Toronto (CA)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- mSphere
- Published
- 2025-01-29
- DOI
- https://doi.org/10.1128/msphere.01078-24
- Citations
- 3
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- U.S. Department of Energy
- U.S. Department of Health and Human Services
- Northwestern University
- University of Pittsburgh
- National Institutes of Health
- Directorate for Biological Sciences
- Office of Science
- Michigan Technology Tri-Corridor
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- Argonne National Laboratory