Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species

Enea Sancho-Vaello, Patrice François, Eve-Julie Bonetti, Hauke Lilie, Sebastian Finger, Fernando Gil-Ortiz, David Gil-Carton, Kornelius Zeth

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.
OriginalsprogEngelsk
Artikelnummer15371
TidsskriftScientific Reports
Vol/bind7
ISSN2045-2322
DOI
StatusUdgivet - 2017

Citer dette

Sancho-Vaello, Enea ; François, Patrice ; Bonetti, Eve-Julie ; Lilie, Hauke ; Finger, Sebastian ; Gil-Ortiz, Fernando ; Gil-Carton, David ; Zeth, Kornelius. / Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species. I: Scientific Reports. 2017 ; Bind 7.
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title = "Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species",
abstract = "Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.",
author = "Enea Sancho-Vaello and Patrice Fran{\cc}ois and Eve-Julie Bonetti and Hauke Lilie and Sebastian Finger and Fernando Gil-Ortiz and David Gil-Carton and Kornelius Zeth",
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Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species. / Sancho-Vaello, Enea ; François, Patrice ; Bonetti, Eve-Julie ; Lilie, Hauke ; Finger, Sebastian ; Gil-Ortiz, Fernando ; Gil-Carton, David ; Zeth, Kornelius.

I: Scientific Reports, Bind 7, 15371, 2017.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species

AU - Sancho-Vaello, Enea

AU - François, Patrice

AU - Bonetti, Eve-Julie

AU - Lilie, Hauke

AU - Finger, Sebastian

AU - Gil-Ortiz, Fernando

AU - Gil-Carton, David

AU - Zeth, Kornelius

PY - 2017

Y1 - 2017

N2 - Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.

AB - Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.

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DO - 10.1038/s41598-017-14206-1

M3 - Journal article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

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