Structural and functional consequences of reversible lipid asymmetry in living membranes

Abstract

Maintenance of lipid asymmetry across the two leaflets of the plasma membrane (PM) bilayer is a ubiquitous feature of eukaryotic cells. Loss of this asymmetry has been widely associated with cell death. However, increasing evidence points to the physiological importance of non-apoptotic, transient changes in PM asymmetry. Such transient scrambling events are associated with a range of biological functions, including intercellular communication and intracellular signaling. Thus, regulation of interleaflet lipid distribution in the PM is a broadly important but underappreciated cellular process with key physiological and structural consequences. Here, we compile the mounting evidence revealing multifaceted, functional roles of PM asymmetry and transient loss thereof. We discuss the consequences of reversible asymmetry on PM structure, biophysical properties and interleaflet coupling. We argue that despite widespread recognition of broad aspects of membrane asymmetry, its importance in cell biology demands more in-depth investigation of its features, regulation, and physiological and pathological implications.

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Fig. 1: The interleaflet asymmetry of the PM bilayer is complex and dynamic.
Fig. 2: Functional roles of reversible PM lipid asymmetry.
Fig. 3: Effects of lipid scrambling on PM physical properties.
Fig. 4: Possible configurations for the interleaflet distribution of cholesterol in the PM.

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Acknowledgements

Funding for I.L. was provided by the US National Institutes of Health/National Institute of General Medical Sciences (R35 GM134949, R01 GM124072, R21 AI146880), the Volkswagen Foundation (93091), and the Human Frontiers Science Program (RGP0059/2019). M.D. was supported by grant F32 GM134704. J.L.S. was supported by grant T32 GM008280.

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Doktorova, M., Symons, J.L. & Levental, I. Structural and functional consequences of reversible lipid asymmetry in living membranes. Nat Chem Biol 16, 1321–1330 (2020). https://doi.org/10.1038/s41589-020-00688-0

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