De novo design of monomeric helical bundles for pH-controlled membrane lysis.
coiled-coil
endosomal escape
membrane disruption
pH responsive
protein design
Journal
Protein science : a publication of the Protein Society
ISSN: 1469-896X
Titre abrégé: Protein Sci
Pays: United States
ID NLM: 9211750
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
10
07
2023
received:
10
05
2023
accepted:
24
08
2023
medline:
30
10
2023
pubmed:
27
8
2023
entrez:
26
8
2023
Statut:
ppublish
Résumé
Targeted intracellular delivery via receptor-mediated endocytosis requires the delivered cargo to escape the endosome to prevent lysosomal degradation. This can in principle be achieved by membrane lysis tightly restricted to endosomal membranes upon internalization to avoid general membrane insertion and lysis. Here, we describe the design of small monomeric proteins with buried histidine containing pH-responsive hydrogen bond networks and membrane permeating amphipathic helices. Of the 30 designs that were experimentally tested, all expressed in Escherichia coli, 13 were monomeric with the expected secondary structure, and 4 designs disrupted artificial liposomes in a pH-dependent manner. Mutational analysis showed that the buried histidine hydrogen bond networks mediate pH-responsiveness and control lysis of model membranes within a very narrow range of pH (6.0-5.5) with almost no lysis occurring at neutral pH. These tightly controlled lytic monomers could help mediate endosomal escape in designed targeted delivery platforms.
Identifiants
pubmed: 37632837
doi: 10.1002/pro.4769
pmc: PMC10578055
doi:
Substances chimiques
Histidine
4QD397987E
Liposomes
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e4769Subventions
Organisme : NIAID NIH HHS
ID : R01 AI165808
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
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