Pro-inflammatory\nS100A8 Protein Exhibits a Detergent-like\nEffect on Anionic Lipid Bilayers, as Imaged by High-Speed AFM

Neuronal cell death\ninduced by cell membrane damage is one of the\nmajor hallmarks of neurodegenerative diseases. Neuroinflammation precedes\nthe loss of neurons; however, whether and how inflammation-related\nproteins contribute to the loss of membrane integrity remains unknown.\nWe employed a range of biophysical tools, including high-speed atomic\nforce microscopy, fluorescence spectroscopy, and electrochemical impedance\nspectroscopy, to ascertain whether the pro-inflammatory protein S100A8\ninduces alterations in biomimetic lipid membranes upon interaction.\nOur findings underscore the crucial roles played by divalent cations\nand membrane charge. We found that apo-S100A8 selectively interacts\nwith anionic lipid membranes composed of phosphatidylserine (PS),\ncausing membrane disruption through a detergent-like mechanism, primarily\naffecting regions where phospholipids are less tightly packed. Interestingly,\nthe introduction of Ca<sup>2+</sup> ions inhibited S100A8-induced\nmembrane disruption, suggesting that the disruptive effects of S100A8\nare most pronounced under conditions mimicking intracellular compartments,\nwhere calcium levels are low, and PS concentrations in the inner leaflet\nof the membrane are high. Overall, our results present a mechanistic\nbasis for understanding the molecular interactions between S100A8\nand the plasma membrane, emphasizing S100A8 as a potential contributor\nto the onset of neurodegenerative diseases.