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An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37

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 speci...

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Autores principales: Kolesinski, Piotr, Wang, Kuei-Chen, Hirose, Yujiro, Nizet, Victor, Ghosh, Partho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212996/
https://www.ncbi.nlm.nih.gov/pubmed/35726694
http://dx.doi.org/10.7554/eLife.77989
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author Kolesinski, Piotr
Wang, Kuei-Chen
Hirose, Yujiro
Nizet, Victor
Ghosh, Partho
author_facet Kolesinski, Piotr
Wang, Kuei-Chen
Hirose, Yujiro
Nizet, Victor
Ghosh, Partho
author_sort Kolesinski, Piotr
collection PubMed
description 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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spelling pubmed-92129962022-06-22 An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37 Kolesinski, Piotr Wang, Kuei-Chen Hirose, Yujiro Nizet, Victor Ghosh, Partho eLife Microbiology and Infectious Disease 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. eLife Sciences Publications, Ltd 2022-06-21 /pmc/articles/PMC9212996/ /pubmed/35726694 http://dx.doi.org/10.7554/eLife.77989 Text en © 2022, Kolesinski et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Kolesinski, Piotr
Wang, Kuei-Chen
Hirose, Yujiro
Nizet, Victor
Ghosh, Partho
An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title_full An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title_fullStr An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title_full_unstemmed An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title_short An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
title_sort m protein coiled coil unfurls and exposes its hydrophobic core to capture ll-37
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212996/
https://www.ncbi.nlm.nih.gov/pubmed/35726694
http://dx.doi.org/10.7554/eLife.77989
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