Abstract
As a model of lipid rafts, the liquid-ordered (Lo) phase formed by sphingomyelin (SM) and cholesterol (Cho) in bilayer membranes has long attracted the attention of biophysics researchers. New approaches and methodologies have led to a better understanding of the molecular basis of the Lo domain structure. This review summarizes studies on model membrane systems consisting of SM/unsaturated phospholipid/Cho implying that the Lo phase contains SM-based nanodomains (or nano-subdomains). Some of the Lo phase properties may be attributed to these nanodomains. Several studies suggest that the nanodomains contain clustered SM molecules packed densely to form gel-phase-like subdomains of single-digit nanometer size at physiological temperatures. Cho and unsaturated lipids located in the Lo phase are likely to be concentrated at the boundaries between the subdomains. These subdomains are not readily detected in the Lo phase formed by saturated phosphatidylcholine (PC) molecules, suggesting that they are strongly stabilized by homophilic interactions specific to SM, e.g., between SM amide groups. This model for the Lo phase is supported by experiments using dihydro-SM, which is thought to have stronger homophilic interactions than SM, as well as by studies using the enantiomer of SM having opposite stereochemistry to SM at the 2 and 3 positions and by some molecular dynamics (MD) simulations of lipid bilayers containing Lo-lipids. Nanosized gel subdomains seem to play an important role in controlling membrane organization and function in biological membranes.
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Acknowledgements
We are grateful to Prof. J. Peter Slotte at Åbo Akademi University and Drs. S. Hanashima, Y. Umegawa, and T. Yasuda at Osaka University, for valuable discussion.
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Some of the research by authors was supported by KAKENHI (grant numbers 19K22257, 16H06315, 20H00405, and 21H04707) to MM and NM, and by a JST ERATO Lipid Active Structure Project grant (JPMJER1005) to MM. The research was also supported by an NIH grant (GM122493) to EL.
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Murata, M., Matsumori, N., Kinoshita, M. et al. Molecular substructure of the liquid-ordered phase formed by sphingomyelin and cholesterol: sphingomyelin clusters forming nano-subdomains are a characteristic feature. Biophys Rev 14, 655–678 (2022). https://doi.org/10.1007/s12551-022-00967-1
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DOI: https://doi.org/10.1007/s12551-022-00967-1