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Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes

Abstract

Lipids are distributed in a highly heterogeneous fashion in different cellular membranes. Only a minority of lipids achieve their final intracellular distribution through transport by vesicles. Instead, the bulk of lipid traffic is mediated by a large group of lipid transfer proteins (LTPs), which move small numbers of lipids at a time using hydrophobic cavities that stabilize lipid molecules outside membranes. Although the first LTPs were discovered almost 50 years ago, most progress in understanding these proteins has been made in the past few years, leading to considerable temporal and spatial refinement of our understanding of the function of these lipid transporters. The number of known LTPs has increased, with exciting discoveries of their multimeric assembly. Structural studies of LTPs have progressed from static crystal structures to dynamic structural approaches that show how conformational changes contribute to lipid handling at a sub-millisecond timescale. A major development has been the finding that many intracellular LTPs localize to two organelles at the same time, forming a shuttle, bridge or tube that links donor and acceptor compartments. The understanding of how different lipids achieve their final destination at the molecular level allows a better explanation of the range of defects that occur in diseases associated with lipid transport and distribution, opening up the possibility of developing therapies that specifically target lipid transfer.

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Acknowledgements

The authors acknowledge funding from the Medical Research Council (grant MR/P010091/1 to L.H.W.), the Wellcome Trust (grant 206346/Z/17/Z to A.T.G.) and the Biotechnology and Biological Sciences Research Council (grant BB/M011801 to T.P.L.).

Reviewer information

Nature Reviews Molecular Cell Biology thanks W. Prinz, F. Maxfield and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors contributed to the conception, writing and reviewing of the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Tim P. Levine.

Supplementary information

Supplementary Box 1

Glossary

Phagophore

The double membrane, also termed isolation membrane, that serves as the initiation site for autophagy. Various ATG proteins are recruited to the phagophore to create the autophagosome.

Lipid desorption

The release of a lipid molecule from a membrane bilayer into the aqueous phase. This process requires a high activation energy for highly hydrophobic lipids, such as glycerophospholipids with two acyl chains.

Oxysterol

An oxidized derivative of cholesterol often created by a specific enzyme. Oxysterols are implicated in various cellular processes including cholesterol homeostasis, metabolism and apoptosis.

Phosphoinositide

A PtdIns-based lipid that is further phosphorylated on the inositol head group. Any of the 3, 4 or 5 positions of the sugar ring can be reversibly phosphorylated to make seven different phosphoinositides. Each phosphoinositide has a specific biological activity related to the proteins that interact with it.

Lipopolysaccharide

(LPS). Also known as endotoxin, LPS is a component of the outer membrane of Gram-negative bacteria with structural and protective functions. It is also a strong pro-inflammatory molecule in the immune system of the host.

Gram-negative bacteria

Group of bacteria that do not stain with the crystal violet used in the Gram staining method. They have two membranes, with lipopolysaccharide confined to the outer leaflet of the outer membrane. A peptidoglycan cell wall is found in the periplasmic space between the outer and inner (cytoplasmic) membranes.

ER–mitochondrial encounter structure

(ERMES). A complex of four proteins localized to endoplasmic reticulum–mitochondrial contact sites. The complex arose in the common ancestor of fungi, animals and protists and has since been lost in animals.

Eugenol

A small hydrophobic alkyl benzene component of plant oils that is toxic via effects on cellular membranes.

Toll-like receptor 4

(TLR4). A single-pass transmembrane protein expressed on the surface of sentinel cells of the immune system. TLRs recognize structurally conserved molecules in pathogenic organisms and initiate immune responses via intracellular signalling cascades, often after endocytosis.

ATP-binding cassette (ABC) transporter

A membrane-embedded protein containing an AAA ATPase domain (see below), where consumption of ATP is linked to pumping of a small molecule across the membrane. In ABCA1 and ABCG1, the pumped substrate is a phospholipid, the movement of which leads to cholesterol flux.

AAA ATPase

A protein that couples energy generated by ATP hydrolysis with conformational changes. The variable amino terminus of these proteins is usually involved in substrate recognition. ATP consumption results in energy input into the substrate so that AAA ATPases can act as pumps (see ABC transporters) or as chaperones that change their substrates’ conformation. One chaperone in yeast is Afg2p, which binds Osh1.

Nuclear steroid receptors

Soluble intracellular receptors for steroid hormones (cortisol, oestrogen, etc.) that consist of a steroid-binding domain and a DNA-binding domain. In response to ligand binding, they translocate to the nucleus and regulate transcription.

γδ T cells

T cell subpopulation mostly found in the gut mucosa that expresses a T cell receptor made of one γ and one δ chain (as opposed to the majority of T cells, which express αβ chains). They have a major role in recognizing lipid antigens.

Abetalipoproteinaemia

Human disorder characterized by dysfunctional absorption of dietary fat caused by autosomal recessive mutations in MTTP, impairing the gut’s ability to synthesize chylomicrons and very-low-density lipoprotein from absorbed fat.

Tangier disease

Congenital lack of high-desnity lipoprotein (HDL) through mutation of both genes coding for ABCA1 so that HDL is not formed. Cholesterol builds up as cholesterol ester deposits in otherwise unusual sites, including tonsils, peripheral nerves and the intestine in addition to causing accelerated atherosclerosis.

Intraluminal vesicle

A vesicle generated during endosome maturation by inward budding of the endosomal limiting membrane. When secretory lysosomes fuse with the plasma membrane, intraluminal vesicles are secreted as exosomes.

Resistance-nodulation-division efflux transporters

This large family of permeases (sometimes called pumps, but almost all devoid of ATPase activity) form selective channels for a very wide range of compounds in all kingdoms of life.

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Further reading

Fig. 1: Box-like LTPs with lids undergo conformational shifts to allow lipid exchange.
Fig. 2: Multisubunit assembly of LTPs.
Fig. 3: Localization of LTPs.
Fig. 4: Mechanisms of generating lipid gradients by LTPs.
Fig. 5: Cholesterol transport by LTPs that is associated with pathology.