The mystery of membrane organization: composition, regulation and roles of lipid rafts

Key Points

  • Cellular membranes are laterally heterogeneous and consist of transient and dynamic domains with varying properties, which prominently include ordered lipid-driven domains that are referred to as lipid (or membrane) rafts.

  • Membrane domains can be induced and regulated by a variety of interactions, which include specific lipid–lipid and lipid–protein interactions, bulk membrane properties, and interactions between membrane components and the underlying cytoskeleton.

  • Advanced microscopy and biochemistry techniques facilitate the study of membrane domains; however, these domains still elude direct in vivo visualization. The multiplicity of possible organizational states and their context-dependent nature most likely account for experimental inconsistencies.

  • Membrane rafts potentially have crucial physiological roles across cell types that range from immune cells to cancer cells.

  • Membrane domains are conserved throughout the domains of life, which supports their functional importance in biological systems.

Abstract

Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large number of studies have focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed (or ordered) membrane domains that selectively recruit certain lipids and proteins. Recent studies have yielded new insights into this mechanism and its relevance in vivo, owing primarily to the development of improved biochemical and biophysical technologies.

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Figure 1: General overview of lateral heterogeneity in the plasma membrane.
Figure 2: Tools to study membrane domain organization, composition and function.
Figure 3: Area coverage of membrane domains and domain size.
Figure 4: Regulation of membrane domains.
Figure 5: Cellular functions of lipid rafts.

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Acknowledgements

C.E. and E.S. are supported by the UK Wolfson Foundation, the UK Medical Research Council (MRC; grant number MC_UU_12010/unit programmes G0902418 and MC_UU_12025), MRC/BBSRC/ESPRC (grant number MR/K01577X/1) and the UK Wellcome Trust (grant Ref. 104924/14/Z/14). E.S. is also supported by an EMBO Long Term Fellowship (ALTF 636–2013) and a Marie Curie Intra-European Fellowship (MEMBRANE DYNAMICS). S.M. is supported by a JC Bose fellowship from the Department of Science and Technology, Ministry of Science and Technology, Government of India, New Delhi, and a Margadarshi fellowship (DBT-Wellcome Trust Alliance grant Ref. IA/M/15/1/502018). I.L. is supported by the Cancer Prevention and Research Institute of Texas (R1215) and the US National Institutes of Health (grant 1R01GM114282).

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Diffraction limit and super-resolution microscopy (PDF 421 kb)

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Glossary

Liquid–liquid phase separation

The coexistence of two phases with distinct compositions and biophysical properties. The components of both phases can diffuse and rearrange rapidly.

Sphingolipid

A class of lipids that comprise a long-chain sphingosine base coupled to a fatty acid chain and often a large polar head group.

Glycosylphosphatidylinositol (GPI)-anchored proteins

Cell surface proteins that are post-translationally modified to carry a GPI moiety as an anchor to the membrane.

Cholera toxin

Proteinaceous toxin secreted by Vibrio cholerae that binds to glycolipids on the cell surface and is responsible for the symptoms of cholera infection.

Single-particle tracking

(SPT). A single-molecule technique in which the motion of individual molecules is tracked with high temporal resolution over relatively long timescales (seconds); these tracks can be used to determine the diffusion properties of a molecule.

Confined diffusion

A mode of diffusion in which the motion of the molecule is transiently arrested by molecular obstacles such as immobile clusters. It is also known as trapped diffusion.

Hop diffusion

A mode of diffusion in which molecules diffuse freely in the membrane except when they encounter a barrier (such as a structure (or structures) associated with actin filaments), the crossing of which hinders diffusion.

Interferometric scattering microscopy

(iSCAT). A microscopy technique to enhance contrast by using the interference from coherent light scattering in the focal plane and of the microscope cover glass.

Fluorescence correlation spectroscopy

(FCS). A single-molecule-based technique in which fluorescence intensity fluctuations from a microscopic observation spot are used to obtain information about molecular diffusion.

Förster resonance energy transfer

(FRET). A fluorescence spectroscopy and imaging technique that is based on the distance-dependent transfer of the excited state energy of a fluorescent donor molecule to a fluorescent acceptor molecule; efficient and widely used to measure intermolecular distances in the range of 1–10 nm.

Amphiphilic properties

Displaying both hydrophilic and hydrophobic character, such as for lipids with hydrophobic acyl chains and hydrophilic head groups.

Raman spectroscopy

A spectroscopy technique whereby vibrational energy of the molecules is used as their 'fingerprint'.

Ganglioside lipid

A class of glycosphingolipids with sialic acid moieties on the head group.

Ceramides

A class of lipids composed of sphingosine and a fatty acid.

Coarse-grained simulations

Simulations that rely on simplified representations of the simulated components.

Hydrogen bonding

Non-covalent chemical bonds between a hydrogen covalently bound to an electronegative atom (as in the -NH group of sphingolipids) and another electronegative atom (such as the oxygen in the -OH group of cholesterol).

Epithelial–mesenchymal transition

A developmental transcriptional programme that imparts mesenchymal characteristics (for example, motility) to epithelial cells.

Viral envelope

The lipid membrane that covers the viral capsid and is derived from the plasma membrane of the host cell.

Caveolae

Specialized invaginations in the plasma membrane that are enriched in caveolin, sphingolipids and cholesterol.

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Sezgin, E., Levental, I., Mayor, S. et al. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat Rev Mol Cell Biol 18, 361–374 (2017). https://doi.org/10.1038/nrm.2017.16

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