Lipid compositions of cells differ according to cell types and intracellular organelles. Phospholipids are major cell membrane lipids and have hydrophilic head groups and hydrophobic fatty acid tails. The cellular lipid membrane without any protein adapts to spherical shapes, and protein binding to the membrane is thought to be required for shaping the membrane for various cellular events. Until recently, modulation of cellular lipid membranes was initially shown to be mediated by proteins recognizing lipid head groups, including the negatively charged ones of phosphatidylserine and phosphoinositides. Recent studies have shown that the abilities of membrane-deforming proteins are also regulated by the composition of fatty acid tails, which cause different degrees of packing defects. The binding of proteins to cellular lipid membranes is affected by the packing defects, presumably through modulation of their interactions with hydrophobic amino acid residues. Therefore, lipid composition can be characterized by both packing defects and charge density. The lipid composition regarding fatty acid tails affects membrane bending via the proteins with amphipathic helices, including those with the ArfGAP1 lipid packing sensor (ALPS) motif and via membrane-deforming proteins with structural folding, including those with the Bin–Amphiphysin–Rvs167 (BAR) domains. This review focuses on how the fatty acid tails, in combination with the head groups of phospholipids, affect protein-mediated membrane deformation.
Cell shape and organelle morphology are determined by the shape of their membranes. Cell membranes are transiently deformed during membrane fusion, fission, and tubule formation during cellular events. These events include organelle division, the formation of inward or outward tubular structures, including endocytic pits and protrusions, and vesicle transport from organelles. Cellular membranes do not have the intrinsic ability to deform into various morphologies, but membrane-deforming proteins regulate cellular and organelle morphology by lipid binding, thereby generating membrane curvature [1–3].
These membrane deformations are dependent on the physical nature of the lipids. Cellular membranes are formed by the bilayer of amphipathic lipids that have high structural diversity. An amphipathic lipid consists of a head group, backbone, and fatty acid tails [4,5]. The head groups of glycerophospholipids were analyzed for their ability to bind to the membrane-deforming proteins. The negatively charged lipids, such as phosphoinositides, phosphatidylserine (PS), and phosphatidic acid (PA), recruit membrane-deforming proteins via their electrostatic and head-group specific interactions. In contrast, it had been believed that the fatty acid tails of glycerophospholipids do not play a role in membrane remodeling because they are buried in the bilayer membrane; thus, it had been assumed that they are not accessible by the membrane-deforming proteins, most of which are soluble cytoplasmic proteins. However, amphipathic helices of proteins are found to be inserted into the hydrophobic core of the lipid bilayer membrane, and thus the fatty acid tails are accessible to the amphipathic helices. Furthermore, the fatty acid tails of lipids are important factors for membrane lipid packing. Therefore, proteins deform membranes to form vesicles and tubules via two modes of interaction; electrostatic interactions between negatively charged lipids and positively charged surfaces of proteins, and hydrophobic insertions, such as amphipathic helices or hydrophobic loops [6–8]. In this review, we present examples of the importance of fatty acid tails in biological membrane morphogenesis.
Lipid composition of the mammalian cell membrane
The mammalian cell membrane consists of sterols and two types of phospholipids, including sphingolipids and glycerophospholipids. Sterols include cholesterol, which does not contain fatty acid tails. Sphingolipids consist of a backbone of sphingoid bases composed of sphingosine and sphingosine-containing lipids, such as ceramide, sphingomyelin (SM), cerebroside, and ganglioside. Glycerophospholipids are the most abundant membrane lipids [4,5]. Glycerophospholipid consists of a glycerol backbone, which is linked to one hydrophilic head and one or two fatty acid tail(s) at the sn1 and sn2 position of the glycerol (Figure 1A). Glycerophospholipids include phosphatidylcholine (PC), phosphatidylethanolamine (PE), PS, and phosphatidylinositol (PI), which are classified by their head groups. Among these phospholipids, PS has a negatively charged head group, which is important for electrostatic interactions with proteins. PS is a constitutive lipid; however, the phosphorylated PIs, which are called phosphoinositides, have more negatively charged headgroups by transient phosphorylation and play essential roles in the regulation of cell shape via the specific binding of phosphoinositide-binding proteins [3,9,10]. The negative charge of phosphoinositides also plays an important role as PS for membrane deformation through interactions with the proteins that regulate other protein activities, which are not the main topic in this review [11,12].
Glycerophospholipids and glycosphingolipids in cell membrane.
Of the glycerophospholipids found in mammalian cells, PC is the most abundant, comprising ∼50% of all the phospholipid molecules [5,13–15], followed by PE (∼20%), PI (∼10%), and PS (∼5%) [5,13–15]. However, the proportion of each glycerophospholipid varies between cell types and organelles. Endoplasmic reticulum (ER) contains more PC and less PS than other organelles, including trans Golgi cisternae, endosomes, and plasma membrane [5,15]. The PS content of mitochondria is very little (1% of their total phospholipid content) . In contrast, the plasma membrane contains a high proportion of PS (10% of total phospholipid) [5,15]. These differences affect membrane remodeling via membrane-deforming proteins .
The localizations of glycerophospholipids and sphingolipids in the two leaflets of the bilayer membrane are asymmetric. PC is enriched in the outer leaflets of the plasma membrane [18,19], while PS and PE are predominantly transported to the cytoplasmic leaflet of Golgi membranes, endosomes, and plasma membrane [18–22]. PS is recruited locally and transiently and functions as a binding partner for the membrane-deforming proteins that interact with negatively charged lipids for vesicle trafficking from these organelles . In contrast, the sphingolipids are mainly localized at the outer leaflet of the plasma membrane or its equivalents [4,19].
Fatty acid composition in glycerophospholipids
Fatty acids are categorized as saturated fatty acids, mono-unsaturated fatty acids (MUFAs), or poly-unsaturated fatty acids (PUFAs). In the mammalian cell, major saturated fatty acids are palmitic acid (C16:0, carbon number: unsaturated bond number) and stearic acid (C18:0). One of the representative MUFA is oleic acid (C18:1), and those of PUFAs are linoleic (C18:2), arachidonic (C20:4), and docosahexaenoic (C22:6) acid [15,23–25] (Figure 1A). The glycerophospholipids with only one fatty acid tail are called lysophospholipids. Most glycerophospholipids have two fatty acid tails, a saturated fatty acid tail at the sn1 position and an unsaturated fatty acid tail at the sn2 position of the glycerol backbone . Therefore, the bulk of lysophospholipid in the bilayer membrane is smaller than that of phospholipids with two fatty acid tails. Lysophospholipids are cone-shaped, which causes positive membrane curvature  (Figure 1C). PC, PS, and PI form cylinder shapes and do not induce membrane curvature (Figure 1D). In contrast, PA is inverted-cone-shaped, causing negative membrane curvature because of its small head group (Figure 1E).
Saturation status of fatty acid tails in glycerophospholipids is thought to affect the deformability of membrane. This happens due to the alteration of membrane rigidity and fluidity related to packing defect, which is defined as the space between lipid molecules. The glycerophospholipids with two saturated fatty acid tails form a tightly packed membrane, while those with unsaturated fatty acid tails form a loosely packed membrane (Figure 1F), as PUFAs reduce membrane rigidity and facilitate the efficient formation of endocytic vesicles [27,28]. Interestingly, the glycerophospholipids with MUFAs form deep packing defects, and those with PUFAs form shallow packing defects, due to the flexible conformation of PUFAs that allow them to fill the space in the packing defect with their fatty acid tails [7,27] (Figures 1F,G).
The influence of fatty acid tails on protein-mediated membrane deformation by amphipathic helix
Amphipathic helices of proteins are cylindrical structures containing hydrophobic and hydrophilic surfaces. Some amphipathic helices are unstructured in solution but form an α-helix upon membrane binding, as described below. Amphipathic helices are buried in lipid bilayer membranes with the hydrophilic side facing the head groups and the hydrophobic side facing the fatty acid tails of the lipids. When an amphipathic helix is inserted into a single layer of bilayer membrane, a change in the area of the single layer of the membrane is induced, thereby inducing membrane deformation of either vesiculation or tubulation [1,17,29] (Figure 2A).
Two major modes of membrane deformation by membrane-binding proteins.
Since packing defects of membrane affects the accessibility of amphipathic helices into the membrane, lipid composition is important for their binding to the membrane. In general, the increase in packing defects due to an abundance of MUFA and PUFA tails is thought to facilitate the binding ability of amphipathic helices (Figure 2B) [30,31]. In contrast, amphipathic helices have difficulty being inserted into tightly packed membranes with an abundance of saturated fatty acids (Figure 2B) [32–34]. Here, we describe many well-studied proteins with amphipathic helices.
ArfGAP1 lipid packing sensor (ALPS) motif
ADP-ribosylation factor GTPase-activating protein1 (ArfGAP1), a GTPase-activating protein for ADP-ribosylation factor 1 (Arf1), promotes COPI vesicle formation from Golgi membrane (Figure 3) [35,36]. ArfGAP1 has the ALPS motif, which is an amphipathic helix in the membrane and works as a sensor for membrane curvature. The hydrophilic surface of the amphipathic helix of the ALPS motif is rich in serine and threonine but not in positively charged arginine and lysine as in the case of the ENTH domain. In the absence of a lipid membrane, the ALPS motif is disordered in solution. In the presence of small liposomes with diameters less than 50 nm, i.e. with higher packing defects, the hydrophobic residues of the ALPS motif are inserted into the packing defects of liposomes, and the ALPS motif forms an amphipathic helix . The preferred size of the liposomes, that the ALPS motif binds to, is altered by the substitution of amino acid residues in the hydrophilic face, suggesting that the recognition of membrane curvature via the hydrophilic face is combined with its possible interactions with hydrophobic space of the lipid bilayer membrane . As an increase in packing defects facilitates the membrane insertion of the ALPS motif, the ALPS motif binds stronger to membranes enriched in C18:1-C18:1 (di-oleoyl:DO) fatty acid tails (with high packing defects) than to the membrane enriched in C16:0-C18:1 (palmitoyl-oleoyl:PO) fatty acid tails . Consistent with in vitro assays, when oleic acid (C18:1) is incorporated into a mammalian cell, ArfGAP1 is localized in the Golgi . In conclusion, packing defect by lipid composition affects the membrane binding of ArfGAP1.
The membrane-deforming proteins in eukaryotic cells.
Arf1 and Sar1p
The amphipathic helices of Arf1 and Sar1p have also been well studied. These two proteins are small GTPases, and the exposure of the amphipathic helix occurs in GTP-bound forms [40,41]. These amphipathic helices are inserted into the membrane, contributing to membrane tubulation and vesiculation. In cells, Arf1 is involved in the formation of Coat protein I (COPI) vesicles from the Golgi apparatus, and Sar1p is involved in the formation of Coat protein II (COPII) vesicles from the ER (Figure 3) [40,42].
The fatty acid tail-dependent deformation of Arf1 has been examined in detail. Arf1 binds weakly to PA , forming tubules that have some constrictions of liposomes containing C18:0-C22:6 PA (stearoyl-docosahexaenoyl:SDPA) . However, Arf1 forms short tubules of liposomes containing C18:1-C18:1 PA (di-oleoyl:DOPA) and almost no tubules of liposomes containing C18:0-C18:0 PA (di-stearoyl:DSPA) . The fatty acid dependency of Sar1p is currently unclear; however, its vesiculation ability is reported to be enhanced by the presence of lyso-PI, a lipid with a single acyl chain, presumably by its cone shape that appears to favor small vesicle formation .
Epsin ENTH domain
Epsin is involved in the formation of clathrin-coated vesicles at clathrin-coated pits (Figure 3) . The amphipathic helix at the N-terminal of the ENTH domain of epsin is disordered in solution but contains abundant basic amino acids on the hydrophilic face of the amphipathic helices, which contributes to binding to the negatively charged phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) [45–48]. The lipid compositions alter the binding affinity of the amphipathic helices to lipid membranes via variations in packing defects and charge density for the amphipathic helix; however, fatty acid dependence has not been reported.
Association of structured membrane-binding domains with glycerophospholipid fatty acid tails
The Bin–Amphiphysin–Rvs167 (BAR) domain is the first characterized structural fold for membrane curvature; however, several other structural folds appear to exist (Figure 2C).
The BAR domains
The BAR domains generate membrane curvature by their curved conformation. The BAR domains are classified into (N-)BAR, F-BAR, and inverse-BAR (I-BAR) domains [3,49–54]. BAR domains typically have three bundled α helices as monomer and form a curved shape upon dimerization. The concave surfaces of BAR and F-BAR domains have an abundance of basic amino acids, which bind to the negatively charged PS and phosphoinositides. In vitro, these domains deform lipid membranes into tubules via their curved structures [55–57].
Some BAR domains contain amphipathic helices at the N-terminus and are thus called N-BAR domains . The structures of the N-BAR domains of amphiphysin and endophilin have higher curvatures and induce membrane tubules of smaller diameters than those of F-BAR domains of CIP4 and FBP17 . N-BAR and F-BAR domains generate membrane tubules around which they form oligomeric scaffolds showing a helical/spiral shape [56,59]. The binding of the BAR domain with the membrane tubule occurs progressively, which appears to indicate progressive oligomerization on the tubules . In cells, F-BAR and N-BAR domains co-operate to induce plasma membrane invaginations, such as clathrin-coated pits . In contrast with F-BAR and N-BAR domains, I-BAR domains have a convex surface enriched in basic amino acids and induce plasma membrane protrusions, such as lamellipodia and filopodia [61–63]. The BAR domains show varied binding preference for tubules of various diameters made by optical tweezers, demonstrating that binding of the BAR domain to membrane depends on the curvature of lipid tubes .
Endophilin N-BAR domain with amphipathic helices
The N-BAR protein endophilins are involved in clathrin-dependent endocytosis (Figure 3) [66–69], clathrin-independent endocytosis of bacterial toxins , and fast-endophilin-mediated endocytosis (FEME) for several GPCRs .
In endocytosis, dynamin execute the scission of membrane for vesicles. An endophilin–dynamin complex performs membrane scission for the production of vesicles . In vitro, this membrane scission by the endophilin–dynamin complex is dependent on fatty acid tail composition. The endophilin–dynamin complex cannot vesiculate membranes containing glycerophospholipids with saturated and MUFA tail (C16:0-C18:1) but can vesiculate membranes with glycerophospholipids with a saturated fatty acid and PUFA tail, including a docosahexaenoic acid (C18:0-C22:6) . As increasing the unsaturation of fatty acid tails decreases membrane rigidity, the complex further facilitates membrane scission in the presence of PUFAs .
Without dynamin, endophilin can deform the membrane into vesicles under low membrane tension, at least in vitro [64,66,73]. Under low membrane tension, endophilin-mediated vesiculation and tubulation depend on the composition of phospholipids in terms of the hydrophilic head groups and the saturation status of fatty acid tails, where the amphipathic helices contribute to membrane binding . The number of amphipathic helices correlate with the vesicle-forming ability . In all these experimental settings, there is some flow of the medium, which might apply force to the membrane. The contribution of force was examined by the sophisticated holding of liposomes by optical tweezer, that is thought to execute the force equivalent to that by motor proteins in cells [60,75]. The scission ability of endophilin functions with other physical forces under membrane tension [60,75]. The oligomeric endophilin forms a diffusion barrier of lipids on the membrane tubules via electrostatic ‘friction' between the endophilin protein and the membrane, which generates the cutting line via the external forces applied to the tubules. Therefore, this membrane scission is called friction-driven scission (FDS). Interestingly, FDS occurs even by and endophilin mutant lacking the amphipathic helices under high membrane tension , suggesting that the contributions of the amphipathic helices are smaller under high membrane tension and friction.
PLCβ1, possible similarity with the BAR domain
There appear to be structural folds that induce membrane curvature other than the BAR domain. Phospholipase Cβ1 (PLCβ1) catalyzes the hydrolysis of PI(4,5)P2. The PLCβ family shares a conserved C-terminal domain in addition to the catalytic core. Interestingly, the structure of the C-terminal domain has been found to be a curved structure that resembles the BAR domain . The C-terminal domain of PLCβ1 can deform the membrane into tubules in vitro . The binding and tubulation ability of PLCβ1 depends on PS and PE, not on the enzyme-substrate PIP2. Although PLCβ1 binds to membranes prepared from lipids with both saturated and unsaturated fatty acid tails, the tubulation ability of PLCβ1 requires lipids with unsaturated fatty acid tails . The membrane-binding/deforming ability of PLCβ1 is involved in the regulation of caveolar morphology (Figure 3) .
The Ankyrin-repeat domains (ARDs), possible structural folds with the amphipathic helix
The ARDs can also be structural folds for membrane curvature due to their curved shapes [78,79]. Most ARDs are designated to the protein–protein interactions; however, some ARDs bind to the membrane [80–82]. ARDs with amphipathic helices deform lipid membranes into tubules and vesicles and are suggested to sense membrane curvature by their possible curved protein structures [80,83]. The ARD of ANKHD1 contains the amphipathic helix at its C-terminal, whereas that of ankycorbin contains the amphipathic helix at its N-terminal [80,83]. ANKHD1 vesiculates the membrane of early endosomes (Figure 3) and ankycorbin forms protrusions for dendritic branches in neurons [80,83]. Since mutations in the amphipathic helices that reduce the interactions with lipids further reduce membrane deformation ability, helix insertion contributes to vesiculation and tubulation of the membrane [80,83]. The ARD-containing protein with the N-terminal amphipathic helix, including ankycorbin, is termed the N-Ank protein . Without the amphipathic helix, the ARD of K1, a vaccinia virus protein, is able to deform membranes into tubules in vitro , while the ARD of the TRPV4 channel associates to PI(4,5)P2 without detectable membrane deformation . However, the role of fatty acid tails in membrane deformation mediated by ARD proteins has not been studied.
Hydrophobic loop insertion and glycerophospholipid fatty acid tails
Other than amphipathic helices, hydrophobic loops on the protein surface are sometimes inserted into membranes. There appears to be no common features of the hydrophobic loops, of which representative examples are described below.
PACSIN2 F-BAR domain
Some of the BAR domains have protrusions on the surface of their proteins. Loops have been reported in the F-BAR domain of PACSIN2 and GAS7. The loops of PACSIN2 are hydrophobic and essential for its binding to the membrane . In contrast, the loops of the F-BAR domain of GAS7 are hydrophilic and, thus, are not inserted into the membrane. Rather, the loops of GAS7 contribute to oligomer formation during phagocytosis .
PACSIN2 is localized to caveolae and regulates caveolar morphology (Figure 3). PACSIN2 interacts with dynamin and EHD2, and is involved in caveolar fission and stability with these proteins [57,86–88]. Caveolae are rich in cholesterol . Caveolae contains PC, which is also a prominent glycerophospholipid in caveolae [90,91]. PS is also abundant in caveolae [22,91]. The depletion of PS leads to the loss of morphology of caveolae . The main fatty acid tails of caveolar glycerophospholipids are oleic acid (C18:1), palmitic acid (C16:0), and stearic acid (C18:0) [90,93]. In addition, in the caveolar membrane, the 1-palmitoyl-2-oleoyl (C16:0-C18:1) PC (POPC) and 1-palmitoyl-2-oleoyl (C16:0-C18:1) PS (POPS) are abundant . The cholesterol dependency of PACSIN2-mediated membrane deformation is an interesting topic for future studies .
Cardiolipin is a unique lipid with four fatty acids. Dynamin-related protein 1 (Drp1) regulates mitochondrial division (Figure 3) . PA and cardiolipin play essential roles in the regulation of mitochondrial division and fusion, and cardiolipin stimulates the oligomerization-related GTPase activity of Drp1 in the mitochondrial division . Drp1 binds equally to PA and cardiolipin via their hydrophilic head groups. Interestingly, Drp1 also recognizes fatty acid tails of PA and cardiolipin and an unstructured loop of Drp1 is responsible for its binding [97,98]. Through this loop, Drp1 strongly binds to PA and cardiolipin having saturated fatty acids [97,98]. Therefore, Drp1 has two binding sites, one for head groups and the other for fatty acids. Furthermore, the GTPase activity of Drp1 is differentially regulated by PA and cardiolipin, and is dependent on their fatty acid tails . Therefore, both head groups and fatty acid tail saturation affect binding and regulate enzyme activity.
GOLPH3 is involved in vesicle trafficking from Golgi to the plasma membrane by regulating membrane curvature of Golgi cisternae (Figure 3) . The structure of GOLPH3 appears to be globular but has a hydrophobic β-loop, which is inserted into the lipid bilayer membrane, thereby resulting in increased membrane curvature for the formation of tubules. GOLPH3 deforms membranes into tubules in a fatty acid-dependent manner. When the membrane contains longer fatty acid tails, the β-loop is inserted into the outer layer alone and the tubular membrane is observed. However, it does not perform tubulation if the membrane contains the short length fatty acid tails.
Deformation of the membrane from outside by lectin–glycolipid interaction
The above-mentioned proteins are localized inside the cells. Interestingly, membrane deformation can be induced from outside the cells. Lectins are proteins that recognize the sugar chains of glycoproteins or glycolipids, which are proteins or lipids with sugar modifications, respectively. The common glycolipids are glycosphingolipids, which include cerebroside and ganglioside, ceramides with glycosylation. According to the Glycolipids and Lectins (GL-Lect) hypothesis , the multivalent bindings of lectins on glycosphingolipids are able to remodel membrane curvature by the clustering of lipids. Such phenomena were found in the secreted proteins and the proteins of pathogens that reached the plasma membrane from outside the cell.
The pathogen Shigella and pathogenic Escherichia coli, including O157, induces diarrhoea and several other symptoms. They produce Shiga Toxins for their entry into host cells. Bacterial Shiga Toxin B subunits (STxB) are pentameric lectin proteins that bind to globotriaosylceramide (Gb3) (Figure 1B), a glycosphingolipid, at the outer leaflet of the plasma membrane (Figure 3). The binding of STxB to Gb3 induces the invagination of the plasma membrane and the reconstituted liposomal membrane . STxB clusters Gb3 to induce membrane invagination by deformation on the outer leaflet. The unsaturated acyl chain of Gb3 is required for invagination by STxB. The fatty acids surrounding Gb3 are also important for invagination .
The Simian virus 40 (SV40) is a polyoma virus that induces cancer and a DNA virus with capsid. The capsid has VP1, a pentameric lectin protein that recognize the glycosphingolipids (Figure 3). VP1 specifically binds to the GM1 (monosialotetrahexosylganglioside) (Figure 1B). Recombinant SV40 capsid with VP1 is able to induce the membrane invagination of the reconstituted liposomes through binding to di-C16 GM1 (DP-GM1) or di-C18:1 GM1 (DO-GM1) but not through binding to C8 GM1 and di-C12 GM1 (DL-GM1) . The invagination of the plasma membrane is an essential step for viral entry into the host cells. Therefore, GM1 with long fatty acid chains is required to induce VP1-mediated membrane invaginations for SV40 entry into the cells.
Vibrio cholerae is the pathogen of cholera and produces cholera toxin. Cholera toxin B subunit (CTxB) is another GM1-binding lectin (Figure 3). CTxB has five GM1-binding sites, similar to the SV40 VP1. CTxB also induces invagination on the liposomal membranes . Interestingly, CTxB is not able to induce the invagination of rigid membranes containing saturated fatty acids, which SV40 VP1 capsid is able to deform into invaginations .
Galectins are produced by mammalian cells and secreted to outside the cells . They are involved in many physiological functions, including immune responses, inflammation, cell migration, and autophagy. Galectins have high affinity for β-galactoside, a glycoside containing galactose, which is found in various glycolipids, including GM1 (Figure 3). Galectins form oligomers that have multiple carbohydrate recognition sites. This enables cross-linking between glycosylated proteins and glycolipids. Among galectins, galectin-3 induces the clathrin-independent endocytosis of β1 integrin and CD44 . Galectin-3 can form invaginations on liposomes containing glycosphingolipid. Galectin-8 also induces the clathrin-independent endocytosis of CD166 . The glycoprotein and glycolipid clustering by galectins drive endocytosis via clathrin-independent carriers (CLIC) [100,107]. Although glycosphingolipids are required for galectin-mediated membrane deformation (according to GL-Lect hypothesis), the role of fatty acid structure in such processes remains to be investigated.
Regulation of membrane curvature by the number of fatty acid tails
The membrane deformations described above is mediated by the protein-mediated assembly of lipid molecules without the enzymatic modification of lipid molecules. However, membrane deformation can also be achieved by the enzymatic modification of phospholipids. The number of fatty acid tails in phospholipids correlates with their spatial occupancy. Therefore, the enzymes that manipulate fatty acid tails affect membrane morphology.
Lysophospholipid acyltransferase adds a fatty acid to lysophospholipids, while phospholipase A2 cleaves the fatty acid tail at the sn2 position in the glycerophospholipids [108,109]. The conversion of phospholipids to lysophospholipids changes the membrane curvature and structure . The activity of phospholipase A2 is required for tubulation of Golgi membrane for vesicle trafficking, and lysophosphatidic acid acyltransferase 3 inhibits membrane tubulation [111,112]. Additionally, the shape of lipid head groups also affects membrane curvature. For example, sphingomyelinases cleave SM to ceramide and phosphocholine, and this increase of inverted-cone-shaped ceramide induces negative membrane curvature [113,114]. These studies indicate that membrane curvature is affected by its lipid composition, which is regulated by enzymatic manipulation of fatty acid tails and head groups of lipids.
Lipid compositions differ among different cell types and organelles. The properties of lipids depend on fatty acid tails and head groups, and the properties affect the depth of packing defects and charge density. The degree of packing defect of a lipid membrane is responsible for its deformability and the insertion of amphipathic helices and hydrophobic loop. However, the exact distribution of the lipids with specific fatty acid tails remains unknown in cells and subcellular organelles. Analysis of lipid composition, including the diversity of fatty acid tails, i.e. saturation, unsaturation, and fatty acid length, will uncover unexpected mechanisms of cellular membrane shaping.
Membranes that are built from lipids of different fatty acid tails have different physical features, including charge density and depth of packing defects.
Membrane-deforming proteins exhibit an altered ability to deform membranes depending on their fatty acid tail composition.
Analysis of lipid composition including the fatty acid tails will uncover unexpected mechanisms of membrane shaping.
The authors declare that there are no competing interests associated with the manuscript.
This work was supported by grants from JSPS (KAKENHI JP15H0164, JP15H05902, JP17H03674, JP17H06006) and JST CREST (JPMJCR1863) to S.S.
M.K., T.I., and S.S. wrote the paper.
We thank all the laboratory members for their helpful discussions.
- ALPS motif
ArfGAP1 lipid packing sensor motif
ADP-ribosylation factor 1
ADP-ribosylation factor GTPase-activating protein1
- COP II
coat protein II
coat protein I
cholera toxin B subunit
dynamin-related protein 1
mono-unsaturated fatty acids
palmitoyl- oleoyl PS
poly-unsaturated fatty acids
stearoyl- docosahexaenoyl PA
Shiga toxin B subunit
Simian virus 40