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Regulation of membrane protein structure and function by their lipid nano-environment

Nature Reviews Molecular Cell Biology volume 24, pages 107–122 (2023)Cite this article

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An Author Correction to this article was published on 03 November 2022

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Abstract

Transmembrane proteins comprise ~30% of the mammalian proteome, mediating metabolism, signalling, transport and many other functions required for cellular life. The microenvironment of integral membrane proteins (IMPs) is intrinsically different from that of cytoplasmic proteins, with IMPs solvated by a compositionally and biophysically complex lipid matrix. These solvating lipids affect protein structure and function in a variety of ways, from stereospecific, high-affinity protein–lipid interactions to modulation by bulk membrane properties. Specific examples of functional modulation of IMPs by their solvating membranes have been reported for various transporters, channels and signal receptors; however, generalizable mechanistic principles governing IMP regulation by lipid environments are neither widely appreciated nor completely understood. Here, we review recent insights into the inter-relationships between complex lipidomes of mammalian membranes, the membrane physicochemical properties resulting from such lipid collectives, and the regulation of IMPs by either or both. The recent proliferation of high-resolution methods to study such lipid–protein interactions has led to generalizable insights, which we synthesize into a general framework termed the ‘functional paralipidome’ to understand the mutual regulation between membrane proteins and their surrounding lipid microenvironments.

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Fig. 1: Inter-relationships between membrane lipidomes, protein structure–function and collective membrane physical properties.
Fig. 2: How collective membrane properties can affect protein organization and function.
Fig. 3: Physical and compositional variations in subcellular membranes.
Fig. 4: Possible modes of lipid interactions with transmembrane proteins.
Fig. 5: The functional paralipidome.

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Acknowledgements

Major acknowledgement goes to K. Levental for insightful feedback and for generating the beautiful and informative figures for the manuscript. We also acknowledge the members of the Levental and Lyman labs for critical reading and enlightening discussions that have polished the ideas in the manuscript. This work was supported by NIH/National Institute of General Medical Sciences (GM134949, GM124072, GM120351), the Volkswagen Foundation (grant 93091) and the Human Frontiers Science Program (RGP0059/2019).

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  1. Department of Molecular Physiology and Biological Physics, Center for Molecular and Cell Physiology, University of Virginia, Charlottesville, VA, USA

    Ilya Levental

  2. Department of Physics and Astronomy, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA

    Ed Lyman

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Glossary

Unfolded protein response

A conserved cellular response to various stresses to the protein folding and secretory systems; can also be induced by lipid perturbations.

MscL and MscS families

Bacterial mechanosensitive channels that open in response to membrane tension, for example, induced by osmotic shock.

PIP2

Phosphatidylinositol 4,5-bisphosphate, a highly charged and tightly regulated lipid type that can associate tightly with integral membrane proteins through both electrostatic and stereospecific interactions.

Sphingolipids

Lipid with sphingoid backbones rather than glycerol. Lipids of this class (for example, sphingomyelin) are common components of eukaryote plasma membranes, interact well with sterols and bind strongly to some proteins.

Native mass spectrometry

A mass spectrometric technique capable of measuring molecular weights of large macromolecules (that is, proteins and their complexes) without fragmentation.

Shotgun lipidomics

A mass spectrometric technique for identifying and quantifying the lipid components of a complex sample (for example, cell membrane) without prior chromatographic separation.

Nanodiscs

An experimental construct containing an integral membrane protein, lipids and a scaffold that solubilizes them. The scaffold can be a protein (MSP) or synthetic polymer (for example, styrene maleic acid).

Gramicidin A

An antibiotic peptide that assembles to form transmembrane pores, dependent on its membrane environment.

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Levental, I., Lyman, E. Regulation of membrane protein structure and function by their lipid nano-environment. Nat Rev Mol Cell Biol 24, 107–122 (2023). https://doi.org/10.1038/s41580-022-00524-4

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