An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
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Curated by eLife
Evaluation Summary:
This manuscript , which focuses on Streptococcus pyogenes M proteins and the antimicrobial peptide LL-37, will be of broad interest to individuals interested in host-pathogen interactions as well as protein-protein interactions.The manuscript provides both structural and functional insight in these areas, including new understanding of how coiled coil proteins can participate in protein-protein interactions and potentially inspiring protein designers and synthetic biologists to design mimetic systems that exploit the principles described here.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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- Microbiology and Infectious Disease (eLife)
Abstract
Surface-associated, coiled-coil M proteins of Streptococcus pyogenes (Strep A) disable human immunity through interaction with select proteins. However, coiled coils lack features typical of protein–protein interaction sites, and it is therefore challenging to understand how M proteins achieve specific binding, for example, with the human antimicrobial peptide LL-37, leading to its neutralization. The crystal structure of a complex of LL-37 with M87 protein, an antigenic M protein variant from a strain that is an emerging threat, revealed a novel interaction mode. The M87 coiled coil unfurled and asymmetrically exposed its hydrophobic core to capture LL-37. A single LL-37 molecule was bound by M87 in the crystal, but in solution additional LL-37 molecules were recruited, consistent with a ‘protein trap’ neutralization mechanism. The interaction mode visualized crystallographically was verified to contribute significantly to LL-37 resistance in an M87 Strep A strain and was identified to be conserved in a number of other M protein types that are prevalent in human populations. Our results provide specific detail for therapeutic inhibition of LL-37 neutralization by M proteins.
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Evaluation Summary:
This manuscript , which focuses on Streptococcus pyogenes M proteins and the antimicrobial peptide LL-37, will be of broad interest to individuals interested in host-pathogen interactions as well as protein-protein interactions.The manuscript provides both structural and functional insight in these areas, including new understanding of how coiled coil proteins can participate in protein-protein interactions and potentially inspiring protein designers and synthetic biologists to design mimetic systems that exploit the principles described here.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Streptococcus pyogenes expresses coiled-coil M proteins that interact with host proteins to promote virulence. One example is M protein association with antimicrobial peptide LL-37. However, since the coiled-coil M proteins lack canonical protein-protein interaction sites, it remained unclear how these interactions occurred. In this manuscript, the authors solved a crystal structure of a complex of LL-37 with the M protein M87. The M87 coiled coil unfurled to exposed its hydrophobic core to interact with LL-37. The authors then aim to show that this mechanism contributed to LL-37 resistance of S. pyogenes. These studies have provided important new information regarding the mechanism of interaction between coiled coil proteins and the alpha helical LL-37. Overall, this is an interesting and convincing …
Reviewer #1 (Public Review):
Streptococcus pyogenes expresses coiled-coil M proteins that interact with host proteins to promote virulence. One example is M protein association with antimicrobial peptide LL-37. However, since the coiled-coil M proteins lack canonical protein-protein interaction sites, it remained unclear how these interactions occurred. In this manuscript, the authors solved a crystal structure of a complex of LL-37 with the M protein M87. The M87 coiled coil unfurled to exposed its hydrophobic core to interact with LL-37. The authors then aim to show that this mechanism contributed to LL-37 resistance of S. pyogenes. These studies have provided important new information regarding the mechanism of interaction between coiled coil proteins and the alpha helical LL-37. Overall, this is an interesting and convincing manuscript. The only major concern relates to the conclusions made based on the E to R substitutions when alanine substitutions yielded no effect on the interactions. The interpretation would be that the electrostatic interaction with the Lysine in LL-37 is not important for the association of M87 with LL-37. The E85R mutant could be causing repulsion effects that are dominant negative. These and associated caveats raise concern that some data may be over-interpreted or requires further analysis.
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Reviewer #2 (Public Review):
This is an excellent paper on an original and exciting discovery from the Ghosh group. The paper is also nicely and concisely written and in a style that will be accessible to a wide audience.
In short, the paper shows that the dimeric coiled coil of a bacterial surface (M) protein can open up to trap a human antimicrobial peptide by forming a new 2:1 heteromeric 3-helix bundle. This is a really neat discovery, which has clear implications for understanding how M proteins protect bacteria against attack by the hosts, and it could also inspire protein designers and synthetic biologists to design mimetic systems along these lines.
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