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NRM-16-084 Re-Re-Submission Final 1 Lipid transfer proteins: the lipid commute by shuttles, bridges and tubes 2 ‡ ‡ 3 Louise H Wong 1, Alberto T Gatta 2 and Tim P Levine1* 4 1 UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK 5 2 Division of Cancer Studies, King's College London, London, SE1 1UL, UK, and 6 Crick Institute, 1 Midland Road, London NW1 1AT ‡ 7 contributed equally to this Work 8 * correspondence to 9 Tim Levine: [email protected] 10 Keywords: 11 cholesterol, cholesteryl ester, lipoprotein, membrane contact site, non-vesicular lipid 12 traffic, organelle, phosphoinositide, phospholipids 13 Word Count (main text): 6650. 14 Abbreviations: 15 CERT – ceramide transport protein, CETP – cholesteryl ester transfer protein, DAG 16 – diacylglycerol, EE – early endosome, ER – endoplasmic reticulum, ERMES – ER- 17 mitochondrial encounter structure, E-Syt – extended-synaptotagmin, FAPP – 18 phosphatidylinositol-four-phosphate adaptor protein, FFAT – 2 phenylalanines in an 19 acidic tract, HDL – high density lipoprotein, LAM – LTP anchored at an membrane 20 contact site, LBP – LPS binding protein, LDL – loW density lipoprotein, LE – late 21 endosome, LPS – lipopolysaccharide, LTP – lipid transfer protein, MCE – 22 mammalian cell entry, NMR – nuclear magnetic resonance, NPC – Niemann-Pick 23 type C, OSBP – oxysterol binding protein, ORP – OSBP-related protein , PA – 24 phosphatidic acid, PC – phosphatidylcholine, PE – phosphatidylethanolamine, PH – 25 pleckstrin homology, PI – phosphatidylinositol, PITP – PI transfer protein, PS – 26 phosphatidylserine, RO – replication organelle , SMP – synaptotagmin-like 27 mitochondrial-lipid-binding protein, StAR – Steroidogenic acute regulatory protein, 28 StARD – StAR domain, StART – StAR-related lipid transfer, TGN – trans-Golgi 29 netWork, TULIP – tubular lipid binding protein, VAP – VAMP associated protein, 30 VLDL – very loW density lipoprotein. 1 31 Abstract 32 Lipids are distributed in a highly asymmetric fashion in different cellular membranes. 33 Only a minority of lipids achieve their final intracellular distribution by selection into 34 the membranes of transport vesicles. Instead, the bulk of lipid traffic is mediated by a 35 large group of lipid transfer proteins (LTPs), Which move small numbers of lipids at a 36 time using hydrophobic cavities that stabilise lipid outside membranes. Despite the 37 first discoveries of LTPs almost 50 years ago, most progress has been made in the 38 last feW years, leading to considerable temporal and spatial refinement in our 39 understanding. The number of knoWn LTPs has increased, With exciting discoveries 40 of multimeric assemblies. Structural studies of LTPs have progressed from static 41 crystal structures to dynamic structural approaches that shoW how conformational 42 changes contribute to lipid handling at a sub-millisecond time-scale. Many 43 intracellular LTPs localise to membrane contact sites, nanoscale zones Where an 44 LTP can form either a shuttle, bridge or tube linking donor and acceptor 45 compartments. Understanding hoW each lipid achieves its final destination at the 46 molecular level alloWs a better explanation of the range of defects that occur in 47 disease, With therapies being developed to target lipid transfer. 2 48 Introduction 49 Cellular integrity requires separation of its contents from its surroundings. Lipid 50 bilayers form the physical boundary that defines a cell’s spatial limits and mediates 51 exchange With the environment. Limiting membranes of many eukaryotic organelles 52 perform similar functions. The lipid composition of each membrane is precisely 53 tailored to these functions1, With a dedicated system of intracellular lipid traffic to 54 achieve different lipid mixtures. There are also lipid transfer systems outside cells, 55 for such basic functions as scavenging lipids from the environment. 56 Traffic of membrane vesicles in eukaryotic cells necessarily moves lipids in the 57 secretory pathWay. HoWever, lipids must also be supplied to compartments that do 58 not receive vesicular traffic, thus requiring an alternative non-vesicular lipid 59 transport2. Even for organelles in the secretory pathWay, lipids are trafficked by non- 60 vesicular means. This might have multiple purposes, including maintenance of lipid 61 compositions that cannot be achieved by vesicles, for example low protein 62 concentrations found in phagophore [G] membranes3. Non-vesicular traffic also 63 allows rapid alterations of lipidome, for example so that the plasma membrane 64 adjusts to environmental changes4. Mammalian cells must also correct any non-ideal 65 lipid movement betWeen donor and acceptor compartments caused by vesicular 66 traffic. These situations call for changes in membrane lipids Without changes in 67 membrane proteins. The tWo main lines of experimental evidence for non-vesicular 68 lipid traffic betWeen compartments linked by vesicular traffic5: (i) speed - 69 phospholipids and cholesterol move bidirectionally betWeen the endoplasmic 70 reticulum (ER) and the plasma membrane much faster (t½=2-5 minutes) than 71 vesicular traffic would allow6–8; (ii) chemical or genetic disruption of the secretory 72 pathWay has little effect on bulk cellular lipid transport betWeen ER and plasma 7,9–11 73 membrane . 74 The hydrophobicity of lipids that allows them to form hydrophobic barriers also 75 prevents their movement across the cytoplasm or betWeen cells. Such movement is 76 entropically unfavourable due to the high activation energy required for the initial 77 step of membrane desorption [G]12,13. The so-called lipid transfer proteins (LTPs) [G] 78 Were postulated to facilitate transfer lipid components of bilayers across the aqueous 79 phase by decreasing this activation energy14. LTPs have since been studied in vitro 80 as enhancers of lipid movement betWeen liposomes. To date hundreds of LTPs have 81 been found in all species, from bacteria to animals. The one feature that unites LTPs 82 is that they provide hydrophobic cavities Where lipids are at a much loWer free 83 energy than if they Were left free in aqueous solution. Most LTPs have been found to 84 form a cavity with a hydrophobic lining, like a protein box, the lipid fitting inside (Fig. 85 1A)15,16. Stoichiometry is typically 1 LTP : 1 lipid, Which is selected both for its 86 headgroup and for its acyl chain length. This implies a specific interaction of lipid With 87 distinct residues within the cavity. Several LTPs are bispecific, meaning they can 88 bind two lipids With different headgroups. LTPs With cavities move lipids one at a 89 time from donor to acceptor, returning either empty to achieve net lipid traffic, or, as 3 90 is the case for many bispecific LTPs, returning With a different lipid to achieve lipid 91 exchange. 92 This revieW Will build on previous surveys of LTPs17 to include considerable recent 93 advances in our understanding of hoW proteins mediate the transfer of the lipid 94 components of membranes. One area of progress is the finding that many are 95 localised to sites Where organelles form narroW gaps that are bridgeable by the LTP 96 itself (typically ≤30 nm). These sites of contact between different organelles 97 (“membrane contact sites”) allow the anchoring points of the LTP to be static, While 98 the domain With the lipid binding cavity transfers lipid cargo between two organelles. 99 An exciting development is the discovery of LTPs that, as opposed to being box-like, 100 form open bridges or closed tubes that cross between membranes, so that lipid 101 moves in the complete absence of protein movement. Other developments include 102 several ideas on how LTPs impose direction on lipid traffic. 103 104 1. Structures and conformation 105 At the structural level, 27 protein families form hydrophobic cavities that transfer 106 membrane bilayer lipids (Table 1). LTPs in the same family can have quite different 107 ligands, even if they share considerable sequence18. In this section, we will briefly 108 describe how LTPs form spaces for hydrophobic lipids. 109 Box-like lipid shuttles 110 The archetypal form of LTP resembles a box, With an internal cavity large enough for 111 one lipid molecule. Lipid transfer requires the LTP to shuttle betWeen donor and 112 acceptor compartments With several steps: membrane docking, lipid extraction, 113 undocking, cytosolic diffusion (Fig. 1B) and then the reverse steps for deposition. 114 Most box-like cavities have residues that move, equivalent to a lid that opens and 115 closes, hoWever some LTPs such as MlaC in bacteria have no lid, exposing the lipid 116 headgroup to the aqueous environment (Fig. 1A)19. Here, we describe the main 117 examples of box-like LTPs. 118 StARkin-superfamily 119 The StARkin superfamily contains domains With similar structure to steroidogenic 120 acute regulatory protein (StAR), the founding member of the StAR-related transfer 121 (StART) family. StARkins, by far the largest grouping of LTPs, have an α-β grip With 122 a hydrophobic cavity20. StAR Was identified first, but the closely related StARD4, is 123 the better understood mechanistically (Fig. 1C, 1D)21. Membrane docking by StARD4 124 is initiated by electrostatic interactions mediated by an electropositive surface patch 125 with anionic membrane lipids. The entrance to the internal cavity, which is near the 126 electropositive patch, is betWeen a long amphipathic a-helix and the so-called Ω1 127 (“Omega-1”) loop22. Nuclear magnetic resonance (NMR) shoWs that the a-helix 128 rotates so that its hydrophobic face engages with the bilayer and the Ω1 loop opens, 129 though it does not embed in the membrane (Fig. 1D)21. The movement of these 4 130 elements is essential for lipid transfer. The application of NMR to these questions is 131 significant because it reveals conformational changes that take place at the highly 132 relevant, but little explored, time-scale of microseconds to milliseconds during Which 133 lipid transfer occurs. 134 Crystal structures indicate that similar movements occur in phosphatidylinositol (PI) 135 transfer proteins (PITPs), Which are bi-specific StARkins, either for PI and 136 phosphatidylcholine (PC) (PITPa/b) or for PI and phosphatidic acid (PA) (PITPNM1, 137 aka Nir2/RdgBa)23,24.
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