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How proteins move lipids and lipids move proteins

Key Points

  • Cellular membranes have distinct compositions that reflect their unique functions. Membrane proteins, synthesized in the cytosol or at the endoplasmic reticulum (ER) membrane, are targeted to the different membranes by structural motifs.

  • Local lipid synthesis and hydrolysis cannot explain the differences in lipid composition between the various membranes and between the two leaflets of the bilayer. The intracellular transport of lipids is selective.

  • Lipids are transported as monomers across membranes. Various families of transporters have been identified that might provide the necessary directionality and lipid specificity.

  • The main transport mechanism for lipids and proteins between organelles is vesicular. Selectivity in these pathways is generated by the lateral segregation of anterograde from retrograde (or resident) components. Lipid sorting is based on a spontaneous phase separation into less fluid sphingolipid–cholesterol domains, that move towards the plasma membrane, and more fluid glycerophospholipid domains, that are preferentially included in transport vesicles towards the ER.

  • Special properties of the lipid domains are recognized by various classes of membrane protein. Some of these are cargo being sorted, others provide directionality to the resulting transport vesicles.

  • Topologically and temporally restricted metabolism of lipids modifies their molecular shape. This seems to be an integral part of vesicle fission and, potentially, fusion.

  • The local production of signalling lipids determines membrane flux by coat recruitment and the activation of fusion. The activity of the responsible enzymes — kinases, phosphatases and phospholipases — is subject to regulation and forms an integral part of the cellular signalling system.

Abstract

Cells determine the bilayer characteristics of different membranes by tightly controlling their lipid composition. Local changes in the physical properties of bilayers, in turn, allow membrane deformation, and facilitate vesicle budding and fusion. Moreover, specific lipids at specific locations recruit cytosolic proteins involved in structural functions or signal transduction. We describe here how the distribution of lipids is directed by proteins, and, conversely, how lipids influence the distribution and function of proteins.

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Figure 1: Mechanisms of lipid transport across and between cellular membranes.
Figure 2: Rates of spontaneous movement across the bilayer and diffusion into the aqueous phase34,85,86,87.
Figure 3: Lipid domains.
Figure 4: Lateral sorting of membrane proteins.
Figure 5: The molecular shape of lipids determines the physical properties of membranes.

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Acknowledgements

We apologize that out of 30,000 PubMed papers on lipid and transport, we quote only 97.

Author information

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Related links

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DATABASE LINKS

scramblase

ABC transporter

ABCB4

ABCB1

Tangier disease

ABCA1

sitosterolaemia

ABCG5

ABCG8

ABCA4

ABCD1

Niemann-Pick type C

NPC1

NPC2

STAR

MLN64

caveolin

FYVE domains

PH domains

AP-1

AP-3

AP-4

GGA

PITP

endophilin

Glossary

EXOCYTIC PATHWAY

Secretory or membrane proteins are inserted into the endoplasmic reticulum. They are then transported through the Golgi to the trans-Golgi network, where they are sorted to their final destination.

ENDOCYTIC PATHWAY

Macromolecules are endocytosed at the plasma membrane. They first arrive in early endosomes, then late endosomes, and finally lysosomes where they are degraded by hydrolases. Molecules can recycle to the plasma membrane from early endosomes, and there are also connections with the exocytic pathway.

LIPID CONCENTRATION

The density of a given lipid at a certain lateral position on one surface of a particular membrane, expressed here as mol% of total lipids. Mol% of phospholipids does not take into account the presence of glycosphingolipids and cholesterol.

VESICULAR TRANSPORT

Transport from one organelle to another, during which cargo-containing vesicles bud from the donor membrane and fuse with an acceptor membrane.

GPI

The general function of GPI anchors is to attach proteins to membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

ABC TRANSPORTERS

Large protein family of transporters that contain an ATP-binding cassette. They hydrolyse ATP and transfer a diverse array of small molecules across membranes.

MULTIDRUG TRANSPORTER

Energy-dependent efflux pump that is responsible for decreased drug accumulation in multidrug-resistant cells. Multidrug resistance is an acquired simultaneous resistance to a wide spectrum of drugs arising from the administration of drugs typically over long periods.

HDL

The smallest type of lipoprotein found in blood plasma, which functions in reverse transport from tissues to the liver.

DISC

The phototransduction apparatus in the outer segment of rod cells contains a stack of discs, each formed by a closed membrane in which rhodopsin molecules are embedded.

DOMAIN

An area in a membrane with a concentration of proteins and/or lipids that is different from its immediate environment. The term 'domain' carries no information about its size relative to the total membrane area, whereas terms such as 'microdomain' or 'raft' suggest that that they cover far less than half of the surface.

COPI VESICLES

Coated vesicles involved in transport through the Golgi and probably in retrograde transport from the Golgi to the endoplasmic reticulum. The COPI coatomer is made of seven subunits (α-, β-, β'-, γ-, δ-, ɛ- and ζ-COP).

CAVEOLA

Flask-shaped, cholesterol-rich invagination of the plasma membrane that might mediate the uptake of some extracellular materials, and is probably involved in cell signalling.

SNARES

(Soluble NSF attachment protein receptor, where NSF stands for N-ethyl-maleimide-sensitive fusion protein.) Proteins required for membrane fusion in exocytosis and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes close together, presumably causing them to fuse.

ARF1

Small GTPase responsible for recruiting different types of coat, leading to vesicle budding.

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Sprong, H., van der Sluijs, P. & van Meer, G. How proteins move lipids and lipids move proteins. Nat Rev Mol Cell Biol 2, 504–513 (2001). https://doi.org/10.1038/35080071

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