Lipoproteins modulate the uptake and biological functionof cationic cell-penetrating peptides across the animal lineage.
Taylor, S. R.; Oluwasesin, T. V.; Salaikumaran, M. R.; Novak, B.; Briner, A.; Ailani, R.; Andrade, P. I.; Onuchic, P. L.; Carmo, O. M. S.; Kim, G.; Blum, J. A.; Galliver, M.; Stuart, C.; Mendez, N.; Patel, V.; Liang, G.-T.; O'Connell, R.; Islam, M. M.; Kashaniasl, Z.; Villar, M. J.; Cao, Y.; Zeng, X.-L.; Porta, L.; Yang, H.; Hohensee, G.; Kavalur, M.; Arey, R. N.; Blutt, S. N.; McRae, E. K. S.; Darabi, R.; Zhang, L.; Jones, K.; Pfisterer, S. G.; Johnston, C. W.; Pollet, J.; Hayashi, M. A. F.; Gitler, A. D.; Lee, H. K.; Holehouse, A. S.; Ludtke, S. J.; Boeynaems, S.
Show abstract
Cationic cell-penetrating peptides (+CPPs) are pervasive killer peptides produced by all animals and found in innate immune systems, venoms and neurodegenerative diseases. Despite their ubiquity, the mechanisms underlying their uptake remain opaque and intensely debated. Here, we interrogate +CPPs spanning 600 million years of animal evolution and identify endocytosis as a conserved/convergent uptake mechanism across cell types and organisms, at physiological concentrations. By combining multiplex imaging, genetic screening, cryo-electron tomography, and biophysical methods, we uncover that +CPPs seemingly universally enter eukaryote cells via 'hitchhiking' on lipoproteins. We further show that the interaction of +CPPs with lipoproteins modulates their antimicrobial function. Combined, our findings establish a unified molecular framework describing a pan-eukaryote cell penetrance mechanism. As hyperlipidemia is a common comorbidity, our findings have direct implications for human health. Lastly, the insights gleaned from this work highlight design principles that may inform the future engineering of peptide-based therapeutics and delivery vehicles.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mechanistic basis of teichoic acid transport by a gatekeeper flippase 95%
- Hepatitis B virus HBx protein masks epigenetic reader Spindlin1 via an inter-molecular zinc finger to subvert transcriptional control 94%
- Structural basis of apoptosis induction by the mitochondrial voltage dependent anion channel 94%
Similar papers in this journal
- IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody 94%
- ProT-Diff: A Modularized and Efficient Approach to De Novo Generation of Antimicrobial Peptide Sequences through Integration of Protein Language Model and Diffusion Model 93%
- Stimulus encoding shapes tactile perception and underlies alterations in autism. 93%
Similar papers in this journal
- Discovering novel calcineurin inhibitors through quantitative mapping of protein-peptide affinity landscapes 95%
- Transient μm scale protein accumulation at the center of the T cell antigen presenting cell interface drives efficient IL-2 secretion 94%
- Genetic, cellular and structural characterization of the membrane potential-dependent cell-penetrating peptide translocation pore 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.