Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides
| Autor: | Shuangshuang Ji, Hao Fei, Xiaolong Chen, Hanjie Liu, Ang Li |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
conformation
Conformational change LAMP-1 lysosomal-associated membrane protein 1 Peptide CMP-Neu5Ac cytidine 5′-monophospho-N-acetylneuraminic acid ANS-Na sodium 8-Anilino-1-naphthalenesulfonate Biochemistry 3Fax-Neu5Ac 3Fax-Peracetyl Neu5Ac Cell membrane Gly-lit glycolithocholic acid anion sensitivity chemistry.chemical_classification IgG Immunoglobulin G Chemistry BafA1 bafilomycin A1 CPP cell-penetrating peptides CAPs cationic amphipathic peptides Peptide Conformation medicine.anatomical_structure Membrane TFE 2 2 2-trifluoroethanol FITC fluorescein isothiocyanate Hydrophobic and Hydrophilic Interactions Research Article IC50 the half inhibitory concentration Anions LAMP-2 lysosomal-associated membrane protein 2 cationic amphipathic peptides CLSM confocal laser scanning microscope Endosomes NY nystatin PI propidium iodide PBS phosphate buffer saline EIPA amiloride LUVs large unilamellar vesicles SAP saporin Amphiphile medicine Membrane activity Amino Acid Sequence CPZ chlorpromazine Molecular Biology IC20 the 20% inhibitory concentration hydrophobicity endosomolytic delivery Cell Membrane Cell Biology Lysosomal-Associated Membrane Protein 1 PSA polysialic acid GRAVY the grand average of hydropathy Biophysics LC50 the half leakage concentration DOPC dioleoyl phosphatidylcholine Peptides DOPG dioleoyl phosphatidylglycerole |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.101364 |
| Popis: | Peptide conformation can change subject to environment cues. This concept also applies to many cationic amphipathic peptides (CAPs) known to have cell membrane lytic or penetrative activities. Well-conditioned CAPs can match the properties of the target membrane to support their intended biological functions, e.g., intracellular cargo delivery; however, the intricacy in such conditioning surpasses our current understanding. Here we focused on hydrophobicity, a key biophysical property that dictates the membrane activity of CAPs, and applied a structure–function strategy to evolve a template peptide for endosomolytic cargo delivery. The template was subjected to iterative adjustment to balance hydrophobicity between its N-terminal linear and C-terminal helical domains. We demonstrate that the obtained peptide, LP6, could dramatically promote cargo cell entry and facilitate cytosolic delivery of biomacromolecules such as FITC-dextran, saporin, and human IgG. Among the evolved peptide series, LP6 has low cytotoxicity and moderate hydrophobicity, exhibits maximum change in helical conformation in response to negatively charged phospholipids, and also shows an apparent aggregational behavior in response to sialic acid enrichment. These attributes of LP6 collectively indicate that its anion-responsive conformational change is a critical underlining of its endosomolytic cargo delivery capability. Our results also suggest that modulation of hydrophobicity serves as a key to the precise tuning of CAP's membrane activity for future biomedical applications. |
| Databáze: | OpenAIRE |
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