Structural and functional dissection of the heterocyclic peptide cytotoxin streptolysin S.
The human pathogen Streptococcus pyogenes secretes a highly cytolytic toxin known as streptolysin S (SLS). SLS is a key virulence determinant and responsible for the beta-hemolytic phenotype of these bacteria. Despite over a century of research, the chemical structure of SLS remains unknown. Recent experiments have revealed that SLS is generated from an inactive precursor peptide that undergoes extensive post-translational modification to an active form. In this work, we address outstanding questions regarding the SLS biosynthetic process, elucidating the features of substrate recognition and sites of posttranslational modification to the SLS precursor peptide. Further, we exploit these findings to guide the design of artificial cytolytic toxins that are recognized by the SLS biosynthetic enzymes and others that are intrinsically cytolytic. This new structural information has ramifications for future antimicrobial therapies.
Mitchell
Douglas A
DA
Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA.
Lee
Shaun W
SW
Pence
Morgan A
MA
Markley
Andrew L
AL
Limm
Joyce D
JD
Nizet
Victor
V
Dixon
Jack E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid; D013297:Streptococcus pyogenes / Q000737:chemistry*; D013301:Streptolysins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000378:metabolism; D014774:Virulence
D001426:Bacterial Proteins; D010080:Oxazoles; D013301:Streptolysins; D013844:Thiazoles; C026050:streptolysin S; C029324:streptolysin S precursor; D011392:Proline