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cancer-cell proliferation; transmembrane helix; extracellular ph; tumor microenvironment; lipid-membranes; drug-delivery; neck-cancer; phlip; translocation; NMR


The pH-low insertion peptide (pHLIP) binds to a membrane at pH 7.4 unstructured but folds across the bilayer as a transmembrane helix at pH similar to 6. Despite their promising applications as imaging probes and drug carriers that target cancer cells for cytoplasmic cargo delivery, the mechanism of pH modulation on pHLIP-membrane interactions has not been completely understood. Here, we show the first study on membrane-associated pHLIP using solid-state NMR spectroscopy. Data on residue-specific conformation and membrane location describe pHLIP in various surface-bound and membrane-inserted states at pH 7.4, 6.4 and 5.3. The critical membrane-adsorbed state is more complex than previously envisioned. At pH 6.4, for the major unstructured population, the peptide sinks deeper into the membrane in a state II' that is distinct from the adsorbed state II observed at pH 7.4, which may enable pHLIP to sense slight change in acidity even before insertion.

Publisher Attribution

Shu, N. S., Chung, M. S., Yao, L., An, M., & Qiang, W. (2015). Residue-specific structures and membrane locations of pH-low insertion peptide by solid-state nuclear magnetic resonance. Nature communications, 6.

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