PT  - JOURNAL ARTICLE
AU  - Kolesiński, Piotr
AU  - Wang, Kuei-Chen
AU  - Hirose, Yujiro
AU  - Nizet, Victor
AU  - Ghosh, Partho
TI  - An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37
AID  - 10.1101/2022.01.11.475926
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.11.475926
4099  - http://biorxiv.org/content/early/2022/01/11/2022.01.11.475926.short
4100  - http://biorxiv.org/content/early/2022/01/11/2022.01.11.475926.full
AB  - 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, which results in its neutralization. The crystal structure of a complex of LL-37 with M87 protein, an antigenic 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 bound M87 in the crystal, but in solution recruited additional LL-37 molecules, 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.Competing Interest StatementThe authors have declared no competing interest.