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The Systematic Analysis of Protein–Lipid Interactions Comes Of PERSPECTIVES and sphingolipids also contain at least one TECHNOLOGY AND TECHNIQUES — INNOVATION fatty acid that can differ in length and/or in its level of unsaturation (which helps to The systematic analysis of protein– determine membrane thickness and fluid- ity), as well as a hydrophilic head group that extends out of the hydrophobic bilayer lipid interactions comes of age into the aqueous phase and can function as a signalling hub. The combination of these Antoine-Emmanuel Saliba, Ivana Vonkova and Anne-Claude Gavin various metabolic building blocks results in a diverse lipid landscape that is exten- Abstract | Lipids tailor membrane identities and function as molecular hubs in all sively exploited by proteins7. Proteins have cellular processes. However, the ways in which lipids modulate protein function adapted a variety of motifs and domains and structure are poorly understood and still require systematic investigation. In that can recognize and sense individual this Innovation article, we summarize pioneering technologies, including lipids and/or more general membrane lipid-overlay assays, lipid pull-down assays, affinity-purification lipidomics and the properties such as curvature, thickness or 7 liposome microarray-based assay (LiMA), that will enable protein–lipid interactions specialized microdomains . Furthermore, protein–lipid interactions can generally be to be deciphered on a systems level. We discuss how these technologies can be divided into three categories, according to applied to the charting of system-wide networks and to the development of new the mechanisms by which these molecules pharmaceutical strategies. recognize each other and the environment in which they are found (FIG. 1). Lipid localization is tightly regulated and charting protein–lipid interactions, and shapes the unique function and proper- a technological effort similar to the one Integral membrane proteins. An essential ties of every cellular membrane1,2. The made for DNA–protein and RNA–pro- type of protein–lipid interaction involves accumulation of discrete phosphoinositide, tein interactions is now needed for lipids. integral membrane proteins, which interact glycerophospholipid, sphingolipid or sterol We believe that a global atlas of protein– with specific lipids within the hydrophobic species defines the identity of the organelle lipid interactions will benefit biology and plane of the membrane. This type of inter- and locally regulates the organization of medicine by shedding light on the role of action is involved in targeting proteins to cellular membranes into microdomains. lipids with ‘orphan’ bioactive activity; by specific organelles8, and it can be used to Over the past few years, much effort has deciphering novel modes of action of lipids modulate protein structure, activity and been dedicated to cataloguing the ‘lipi- through their interactions with proteins; function9,10. For example, the protein p24, dome’, which is now estimated to contain and by understanding the misregulation of which is a component of the coat protein I more than 40,000 different lipid species lipids in disease. In this Innovation article, (COPI) machinery, has a transmembrane (see the LIPID MAPS Structure Database we summarize the recent technological segment that specifically and exclusively (LMSD))3; however, the biological role of advances that will allow global protein– binds to one sphingomyelin species, only a few of these lipids is known. lipid interactions to be mapped on a sys- SM18 (REF. 11). This interaction, which Lipids function predominantly through tems level and open up new pharmaceutical involves the head group and backbone of their interactions with proteins. Indeed, strategies. We also discuss the future needs the sphingolipid and a signature sequence protein–lipid interactions are involved in all and challenges involved in the integra- (VXXTLXXIY; where X indicates any biological processes and are of paramount tion of diverse, orthogonal approaches for amino acid) within the transmembrane interest in pharmaceutical discovery, as studying the regulation of proteins by lipids domain of p24, induces p24 oligomeriza- 60% of drug targets are located at the cell in biology and medicine. tion and activation to regulate COPI- surface or in other cellular membranes4,5. dependent vesicular transport. Integral Integral and peripheral membrane proteins The interaction landscape membrane proteins, however, are challeng- account for one-third of the full proteome6; Lipids are well known for their amphi- ing to study, and our current knowledge is however, research into the mechanisms that pathic nature and their capacity to form limited to a few prototypic examples that are used by lipids to regulate protein func- membrane bilayers. Their structures are have generally been investigated using tion and structure — and, ultimately, to diverse because of their distinct chemical advanced biochemical, biophysical or shape cell physiology — has been restricted backbones, which are composed of glycerol structural methods that cannot easily be to a small number of proteins, with a strong in the case of the glycerolipids and glyc- scaled up. More generic approaches — that focus on mechanistic insights. This gap in erophospholipids, sphingoid long-chain is, those that are applicable to all types of our knowledge is due to a lack of meth- bases for the sphingolipids and isoprene for protein–lipid interactions — are needed ods that are amenable to systematically the sterols (BOX 1). Glycerophospholipids (see below). NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 16 | DECEMBER 2015 | 753 © 2015 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Box 1 | Liposomes: surrogates of biological membranes Peripheral membrane proteins. Another important type of interaction involves the Liposomes (also called phospholipid vesicles), which are closed vesicles comprising a bilayer of recruitment of soluble proteins to the cell 82,83 amphiphilic molecules, are in vitro mimics of natural membranes . A large variety of lipids are periphery of biological membranes. Several available from multiple suppliers (see Supplementary information S1 (table)), notably glycero­ domains recognize specific lipid head phospholipids, phosphoinositides, sphingolipids and sterols (the structures of the major lipid 12 species are shown in the figure, part a), although the commercially available lipid repertoire is still groups (for example, pleckstrin homology far from covering the range of natural lipids. Each lipid category is hierarchically organized around (PH) domains recognize phosphoinositide a core structure that is defined in a species on the basis of a modification of the head group phosphates and the C2 domain of lactadherin (for glyceropho­spholipids the modifications are labelled ‘R’ in the figure, part a) or a chemical recognizes phosphatidylserine) and/or spe- modification in the core structure (for example, in the sphingolipids and sterols). Lipids dissolved in cific membrane features (for example, epsin organic solvents can be stored in glass vials at -20 °C under argon or nitrogen, and the quality of the amino‑terminal homology (ENTH) and BAR initial lipid composition and any further degradation over time can be monitored, conveniently, domains recognize membrane curvature)12–14. by matrix-assisted laser desorption/ionization–time of flight (MALDI–TOF) mass spectrometry. Thus, lipids and other membrane attributes A thin-layer chromatography spotter can be used for the high-throughput and automatic handling function as second messengers to control the of lipids, because they are resistant to organic solvents16,39, but these robots are limited by poor spatiotemporal recruitment and activation of spatial resolution. 14 Liposomes are normally classified by their size and the number of bilayers that they contain specific protein effectors . A key example is (unilamellar liposomes have a single bilayer; multilamellar liposomes have multiple bilayers)82 and the Ser/Thr kinase AKT1, which is activated are usually designated as SUVs (small unilamellar vesicles, which have a diameter of <100 nm), LUVs by its recruitment to membranes through (large unilamellar vesicles, which have a diameter of ≤1 μm) or GUVs (giant unilamellar vesicles, which its specialized PH domain that recognizes have a diameter of >1 μm). The preparation of liposomes in general82, and of GUVs specifically83, phosphatidylinositol‑3,4,5‑trisphosphate has been reviewed elsewhere; several popular and successful methods are now used (see the figure, (PtdIns(3,4,5)P3) or PtdIns(3,4)P2; both lipids part b). These protocols are suitable for preparing a few liposome types, but they are difficult to scale are produced locally by phosphoinositol up because of major technical limitations: the protocols are time-consuming and require large 3‑kinase (PI3K)14. Domains involved in the amounts of starting material; each lipid mixture needs to be optimized; and the liposomes cannot be recruitment of proteins to the periphery of stored long-term. The introduction of a method that allows GUVs to be produced upon the 84 membranes were the focus of the first system- hydration of an agarose film has opened up new possibilities, as this protocol can be integrated 15 into a microarray format to form hundreds of liposome types in parallel39 and can be further atic protein–lipid interaction survey (see developed to create proteoliposome arrays42 (that is, liposomes into which membrane proteins have below). However, despite
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