ArticleBiochemistry2013
Aspartate embedding depth affects pHLIP's insertion pKa.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Improving the Estimation of pThe journal of physical chemistry. B · 2026Article
- Membrane Composition Reshapes the Folding Landscape of a pH-Responsive Peptide.The journal of physical chemistry letters · 2026Article
- Improved acid-driven inhibition of effector T cell function by a pHLIP variant-conjugated PD-L1.Scientific reports · 2025Article
- Selective Recruitment of Antibodies to Cancer Cells and Immune Cell-mediated Killing via In Situ Click Chemistry.ChemMedChem · 2024Article
- Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides.Frontiers in pharmacology · 2024Review
- Promoting the activity of a receptor tyrosine phosphatase with a novel pH-responsive transmembrane agonist inhibits cancer-associated phenotypes.Protein science : a publication of the Protein Society · 2023Article
- Length matters: Functional flip of the short TatA transmembrane helix.Biophysical journal · 2023Article
- Increasing the Realism ofJournal of chemical theory and computation · 2022Article
- CaProtein science : a publication of the Protein Society · 2022Article
- Roles of key residues and lipid dynamics reveal pHLIP-membrane interactions at intermediate pH.Biophysical journal · 2021Article
- pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity.Journal of medicinal chemistry · 2020Article
- Article
- Divalent Cations and Lipid Composition Modulate Membrane Insertion and Cancer-Targeting Action of pHLIP.Journal of molecular biology · 2019Article
- Activity and characterization of a pH-sensitive antimicrobial peptide.Biochimica et biophysica acta. Biomembranes · 2019Article
- Ions Modulate Key Interactions between pHLIP and Lipid Membranes.Biophysical journal · 2019Article
- Site-Specific Peptide Probes Detect Buried Water in a Lipid Membrane.Biophysical journal · 2019Article
- pH-dependent thermodynamic intermediates of pHLIP membrane insertion determined by solid-state NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Article
- Membrane-Induced p KJournal of chemical theory and computation · 2018Article
- Comparison of lipid-dependent bilayer insertion of pHLIP and its P20G variant.Biochimica et biophysica acta. Biomembranes · 2018Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
We have used the pHlow insertion peptide (pHLIP) family to study the role of aspartate embedding depth in pH-dependent transmembrane peptide insertion. pHLIP binds to the surface of a lipid bilayer as a largely unstructured monomer at neutral pH. When the pH is lowered, pHLIP inserts spontaneously across the membrane as a spanning α-helix. pHLIP insertion is reversible when the pH is adjusted back to a neutral value. One of the critical events facilitating pHLIP insertion is the protonation of aspartates in the spanning domain of the peptide: the negative side chains of these residues convert to uncharged, polar forms, facilitating insertion by altering the hydrophobicity of the spanning domain. To examine this protonation mechanism further, we created pHLIP sequence variants in which the two spanning aspartates (D14 and D25) were moved up or down in the sequence. We hypothesized that the aspartate depth in the inserted state would directly affect the proton affinity of the acidic side chains, altering the pKa of pH-dependent insertion. To this end, we also mutated the arginine at position 11 to determine whether arginine snorkeling modulates the insertion pKa by affecting the aspartate depth. Our results indicate that both types of mutations change the insertion pKa, supporting the idea that the aspartate depth is a participating parameter in determining the pH dependence. We also show that pHLIP's resistance to aggregation can be altered with our mutations, identifying a new criterion for improving the performance of pHLIP in vivo when targeting acidic disease tissues such as cancer and inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.