Biological Membranes

Description of the lipid composition



membranes

Eukaryotic plasma membranes

Eukaryotic cells are highly compartmentalized. Plasma membranes (PM) and membranes of intracellular organelles are characterized by morphological complexity, structural asymmetry, and high lipid diversity. The compositional diversity of lipids in different intracellular membranes is vital, therefore its maintenance consumes considerable amount of ATP and requires proteins encoded by up to ~5% genome [1].

membranes

Membranes of higher eukaryotes are composed of more than 1,000 chemically different types of lipid molecules, which include glycerophospholipids with diverse head groups and acyl chains, tissue-specific sphingolipids (SLs) with more than 500 carbohydrate structures as head groups, and sterols. The main eukaryotic glycerophospholipids are: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), cardiolipin (CL), phosphatidyc acid (PA), and phosphatidylinositol (PI) [1]. The major SLs are sphingomyelin (SM) and glycosphingolipids [2] with mono-, di- or oligosaccharide chains (e.g. sialic acids in gangliosides) [3]. In low eukaryotes, such as yeast, the lipid diversity is lower: membranes contain different glycerophospholipids, but only four types of sphingolipids and distinct sterols [4]. Sterols and sphingolipids are the exclusive lipids of eukaryotes that facilitate lipid and protein segregation and formation of internal membranes with distinct lipid and protein composition [5-7]. In mammalian cells, PMs are covered by the fuzzy coat of glycocalyx composed by carbohydrate moieties of glycoproteins and membrane glycolipids [8], which replaces the rigid cell wall structure of bacteria, plants, and fungi.

PMs of mammalian cells are mainly composed of PC (30-50 mol%), PE (25-40 mol%), SM (1-15 mol%), PS(5-10 mol%), PI (1-15 mol%), and cholesterol (30-40 mol%), whose relative amount varies in different cell types [7, 9]. The lipid distribution in PM is highly asymmetric with 75-80% of the PC and SM in the outer leaflets and 80% of PE, PA, PI, and almost all PS in the cytosolic leaflet [10]. The most abundant PM lipid is a zwitterionic PC with cylindrical molecular geometry that spontaneously forms planar lipid bilayers. Some lipids have conical shape due to the small size of the headgroup (e.g. PE, CL, diacylglycerol) or hydrocarbon tail (e.g. PA). These lipids spontaneously form non-bilayer hexagonal or cubic lipid phases [11, 12]. Incorporation of non-bilayer lipids into membranes imposes a curvature stress that affects membrane protein structure, function, oligomerization, and promotes membrane fusion, fission and budding [13-15].

membranes

The high level of densely packed SLs and cholesterol increases the rigidity and stability of the PM [1]. The preferential association of PM proteins with SLs, sterols, and saturated glycolipids ensure their lateral segregation and formation of detergent-resistant microdomains, so-called lipid rafts [16-18]. Stability of these nanoclusters depends on lipid-protein interactions, protein oligomerization, ligation and/or scaffolding, as well as interaction with the actin cytoskeleton [19]. Formation of microdomains is an essential step in vesicular trafficking, a phenomenon exclusive to eukaryotic cells [17]. The phase segregation, raft clustering into a platform, and generation of vesicular raft carriers is the main mechanism for protein and lipid sorting and trafficking to different parts of the PM of polarized cells, in addition to coat- and adaptor-mediated mechanisms [7, 20, 21].

Eukaryotic membranes contain distinct phosphoinositides which selectively map cellular and intracellular membranes. For example, PtdIns(4)P is specific for the (trans)-Golgi network, PtdIns(3)P is present on early endosomes, PtdIns(3,5)P2 on late endososmes, PtdIns(4,5)P2 is the most abundant on the PM [22]. Phosophoinositides participate in signaling and protein sorting by recruiting membrane-targeting protein domains [23]. For example, PH domains bind various phosphoinositides, FYVE domains selectively bind PtdIns(3)P, ANTH/ENTH domains bind PtdIns(4)P, PtdIns(5)P, PtdIns(4,5)P2, or PtdIns(3,5)P2, and PX domains bind PtdIns(3)P, PtdIns(3,4)P2, or PtdIns(4,5)P2.


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Endoplasmic reticulum membrane

Endoplasmic reticulum (ER) is the main organelle where lipid and protein biosynthesis occurs. ER form network of interconnected sacs or cisternae held together by cytoskeleton. There are two types of ER: rough ER and smooth ER. Cisternal space of rough ER is continuous of the perinuclear space, while membranes of rough ER are covered by ribosomes bound to translocon complex that perform synthesis and translocation across membranes of transmembrane and secretory proteins. Smooth ER participates in lipid and carbohydrate metabolism and detoxification. In contrast to other cellular membranes, ER membranes have a nearly symmetric lipid distribution between both leaflets and a relatively loose packing of lipids that are mainly composed of PC (50-70%), PE (15-30%), PI (~10%), PS (~7%) with a minor level of other lipids and cholesterol [1, 7, 9]. These properties of the lipid bilayer facilitate insertion of newly synthesized lipid and protein molecules into ER membranes. Lipids and proteins are then distributed from ER to PM, endosomes, lysosome, and mitochondria.

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Membranes of Golgi apparatus

membranes
membranes

Golgi apparatus is made of stacks of vesicular cisternae with tubular connections that participate in vesicular transport in the secretory, lysosomal, and endocytic pathways. Glycosylation enzymes from Golgi complex attach sugar moieties to proteins moving from ER to the plasma membrane via Golgi apparatus in a direction from the cis-Golgi network (CGN) to the trans-Golgi network (TGN). From cisternae of TGN, proteins are packaging into vesicles destined to lysosomes, secretory vesicles, or plasma membrane. TGN is a main sorting station in the secretory pathway which confers 5 to 10-fold enrichment of sphingolipids and sterols in PM as compared to ER [1]. TNG have highly asymmetric lipid distribution between leaflets with PS and PE accumulated in the inner leaflet at the cytoplasmic side, and PC and SM in the outer leaflet, similar to PM of mammalian cells. TGC membranes of yeast are primarily composed of PC (20-30%), PI (25-30%), glycosylinositol-phosphoceramide (11%), and ergosterol (10-22%) [24].


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Late endosome and lysosome membranes

The lipid composition of early endosomes resembles those of PM. Multivesicular bodies (MVBs), which are spherical vesicles with a diameter of ~400-500 nm, originate from early endososmes by the inward invagination of the limiting membrane into the endosomal lumen followed by bud scission [25]. MVBs fuse with either PM, where their content is released into extracellular space (as exosomes), or with late endosomes that transform into lysosomes, where their content undergoes degradation. MVBs targeted to degradation are presumed to undergo the monoubiquitination of proteins and release into the lysosome lumen. Late endosomes are more pleiotropic in shape with cysternal, tubular and multivesicular regions. Internal membranes of late endosomes are characterized by the high amount (up to 70% BMP) of non-bilayer phospholipid, bis-(monacylglycero)-phosphate (BMP) [26]. BMP promotes membrane fusion during acidification of maturing endosomes [27]. In addition, ceramide, which is present in raft of late endosome membranes, due to its cone-shaped structure spontaneously induces negative curvature of the lipid bilayer, thus promoting vesicle budding and fusion [28].

membranes

Lysosomes are spherical (diameter of 100-1200 nm) acidic (pH ~4.5 in lumen) vesicles that contain >50 hydrolytic enzymes capable of breaking protein, lipids, carbohydrates, and nucleic acids. Lysosomes are not only “waste disposal system” but are also involved in secretion, repair, signaling, and energy metabolism. The limiting membrane of lysosomes might be protected against hydrolytic degradation by the glycocalix formed by glycosylated transmembrane proteins on the lumenal surface of the lysosomal membrane, while the major lipid of internal membranes, BMP, is a poorly degradable phospholipid because it has an unusual sn-1-glycerophospho-sn-1’-glycerol stereoconfiguration [26].


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Membranes of extracellular vesicles

Exosomes (30-100 nm in diameter) and secreted extracellular microvesicles (150-1000 nm in diameter) are involved in genetic communication between cells (contain RNAs), antigen presentation (contain MHC I, MHC II, CD86), neuronal communication, tissue physiology and regeneration [29]. Microvesicles are generated by blebbing of the PM, while exosomes are formed by fusion of multivesicular endosomes or MVBs with PM [30, 31]. The lipid composition of the exosomal membrane has features reminiscent of PM raft domains with the increased ratio of certain lipids, such as SM, PS, PC, PI, ganglioside GM3, ceramide, and cholesterol [32]. However, content of BMP, a specific lipid of MVB, is not enriched.


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Lipid droplets

Lipid droplets (LDs) are subcellular structures (300-1000 nm in diameter) that function not only as storage depots, but also as metabolically dynamic organelles [33]. LDs harbor only a monolayer of phospholipids derived from ER that surrounds the hydrophobic core composed of triacylglycerols and steryl esters. LD surface has numerous proteins that are also present in ER membranes. Lipids of LDs are enriched in the anionic phospholipids and PI, as double-unsaturated lipid species, as compared to ER lipids. The protein content is rather low with most proteins involved in lipid metabolism.


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Peroxisomal membrane

membranes

Peroxisomes are involved in metabolism of hydrogen peroxide and various catabolic reactions (e.g. β-oxidation of fatty acids), biosynthetic reactions (e.g. biosynthesis of plasmalogens), and in the glyoxylate cycle. Peroxisome have a single membrane that enclose matrix rich in diverse enzymatic proteins [33]. Membrane of peroxisome from budding yeast is composed of PC (48.2%), PE(22.9%), PI (15.8%), CL (7%), and a few membrane proteins involved in protein transport [34]. Membranes of liver peroxisomes contain phospholipids: PC (36-45%), PE (47-50%), and PI(4-6%); free fatty acids, triglycerides and cholesterol [35]. Peroxisomes are considered to be autonomous organelles that can grow and divide. In yeast most peroxisomes are formed by fission of existing peroxisomes with help of dynamin-related proteins [33].


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Nuclear membranes

membranes

A nuclear membrane or nuclear envelope (NE) is the double-layered membrane which separates the genetic material and nucleolus from the cytoplasm in eukaryotic cells. Inner nuclear membrane (INM) and outer nuclear membrane (ONM) are continuous with the rough ER membrane and both are covered in ribosomes [36]. Membranes of NE are composed of phospholipids at proportions close to those in ER (e.g. ~45% PC, ~27%PE, ~15%PI, 6% PS, 2% PA in budding yeast)[34].


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Mitochondrial outer membrane

Lipid composition of the MOM differ from that in the outer membranes of Gram-negative bacteria: MOM contain phospholipids in both leaflets, lacks LPS, and are composed of PC (46-55%), PE (28-33 mol%), PI (9-13 mol%), and small amount of PS (ə-2 mol%), and CL (1-6%) [37, 38].

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Mitochondrial inner membrane

Mitochondrial inner membranes (MIM) form highly folded structure with cristae, the internal mitochondrial compartments. The lipid composition of MIM is similar to that of the bacterial inner membranes, with the large amount of non-bilayer forming lipids (PE and CL). MIM contains PC (~40 mol%), PE (25-40 mol%), PI (~16%), and CL (10-23%) as major phospholipids [37-39]. Unlike the variable lipid composition of membranes in diverse eukaryotic cells, the phospholipid levels of the MIM is rather constant in different tissues, and its alterations are not tolerated but cause diseases [40]. Negatively charged CL is an essential component that regulates various mitochondrial functions [41]. In particular, CL is critically required for biogenesis and stabilization of respiratory chain supercomplexes [42, 43], as well as for mobilization of cytochrome C on IMM, thus preventing the appoptosis [44]. Depletion of CL due to absence of tafazzin, an enzyme essential for the formation of CL, causes the severe mitochondrial dysfunction with defective ATP formation, which is manifested as Barth syndrome [45].


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Thylakoid membrane

membranes

Thylakoid membranes form compartments inside chloroplasts and their postulated ancestors, cyanobacteria. This is the site of all light-dependent processes of phytosynthesis, i.e. the conversion of light energy into chemical energy. Thylakoid membranes are organized in grana with stacked architecture and sacs connecting neighboring grana. Such structural organization of folded membranes has functional significance for light adaptation, optimal holding of antenna assembly, and spatial organization and separation of two photosystems and ATP synthase [46].

The characteristic features of photosynthetic membranes of thylakoids and cyanobacteria are: the unusual abundance of non-phosphorus galactoglycerolipids, the underrepresentation of phospholipids and the presence of anionic sulfolipids [47]. Thylakoid membrane lipids include a sole phospholipid, PG, and three glycolipids: monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG), and sulfoquinovosyl diacylglycerol (SQDG). The composition of lipids co-crystallized with cyanobacteria Photosystem II (3bz1) (11 MGDG, 7 DGDG, 5 SQDG and 2 PG) and the preferential location of acidic lipids at the stroma leaflet reflects the relative contents (~45%, ~25%, ~15-25%, 5-15%, respectively) and asymmetric distribution of these lipids in thylakoid membranes [48].

Thylakoid membranes are crowded by protein complexes with limited regions of free phospholipids (lipid:protein ration is ~1:4), so proteins account for up to ~80% of the dry mass [49]. High content of proteins that bind non-bilayer MGDG lipid stabilizes the structure of thylakoid membranes and prevents the formation of a non-lamellar phase [49].


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Membranes of Gram-negative bacteria

The cell envelope of Gram-negative bacteria is composed of two membranes with quite different composition and properties, the inner membrane (IM) and the outer membrane (OM). OM and IM are separated by a periplasmic space containing a thin layer (2-3 nm) of peptidoglycans, also known as mureins.

membranes

Outer Membrane

Unlike a typical phospholipid bilayer, the bacterial OM has extremely asymmetric structure where the inner leaflet is composed of glycerophospholipids, primarily PE and PG, and the outer leaflet contains a unique glycolipid, lipopolysaccaride (LPS) [50, 51]. LPS is composed of lipid A, and long polysaccharide chain subdivided into the acidic inner core, outer core, and O-antigen region. The structure of the LPS leaflet is stabilized by ionic interactions between anionic groups of lipid A and divalent cations that bridge and neutralizes negative charges, as well as by H-bonding interactions between numerous donor and acceptor groups of lipids and core oligosaccharides [50]. Lipid A phosphate groups forms ionic pairs with basic amino acids of outer membrane proteins, which also stabilize the membrane structure. The LPS leaflet of OMs has a gel-like structure with a highly ordered, nearly crystalline arrangement of saturated acyl chains of the lipid A (usually 6 chains per lipid) [52]. It is also characterized by increased rigidity and reduced penetrability as the consequence of the stronger lateral intermolecular interactions between lipids and numerous H-bonds and ionic pairs between lipid A and proteins [50]. In thermophilic bacteria Thermus thermophilus, the OM consists of glycolipids and phosphoglycolipids, not LPS, which may increase membrane stability at high temperatures [53]. The extracellular surface of Gram-negative bacteria is covered by high-molecular-weight (capsular) polysaccharides and exopolysaccarides firmly attached to the cell. Some bacteria have additional protective S-layer on the cell surface formed by self-assembling glycoproteins that contact with LPS [54].

Inner Membrane

The IM of Gram-negative bacteria are less complex than PM of eukaryotic cells, having around a hundred lipid species. Lipids of many Gram-negative bacteria are composed mainly of PE and PG with some amount of PI and CL. The lipid composition of the IM from E. coli is one of the simplest found in nature. It consists of two major phospholipids, PE and PG, and traces of CL (PE/PG/CL ratio of 71.39:23.36:5.25 mol/mol%)[55] with only three major fatty acids (16:0, 18:1, 16:1) [56]. Anionic lipids are known to influence the membrane protein topology in E. coli [57-60]. To adapt to different environmental conditions and to maintain the optimum fluidity of membranes, bacteria produce a large variety of membrane lipids with different fatty acids. In addition to adjusting the level of desaturation of lipid acyl chains in response to temperature, bacteria can synthesize lipids that incorporate methyl, hydroxyl and cyclic groups [56, 61]. Unlike eukaryotic membranes, bacterial IMs generally do not contain conventional sterols. However, as an adaptation to extreme environmental conditions, some bacteria and blue-green algae produce hopanoids, hydrophobic pentacyclic triterpenoids that are structurally related to cholesterol. Bacterial hopanoids supposedly regulate fluidity and permeability of the lipid bilayer, as well as cell sensitivity to pH, detergents and antibiotics [62].


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Cell membrane of Gram-positive bacteria

The cell envelope of Gram-positive bacteria is composed of a cytoplasmic membrane surrounded by a cell wall. The cell wall consists of: (a) peptidoglycans, linear polysaccharides cross-linked by short peptides; (b) secondary cell wall polymers, such as teichuronic acids, teichoic acids, other neutral or acidic polysaccharides (e.g. lipoglycans); (c) S-layer formed by proteins covalently or non-covalently attached to peptidoglycans [54, 63]. Teichoic acids are charged anionic polyol phosphates, which confer a negative charge to the cell wall. Most monoderm bacteria have a thick peptidoglycan layer (20-80 nm) that retains the Gram (crystal violet) staining [63].

Lipid composition of bacterial membranes is variable and depends on the environmental conditions [61]. Bacteria from genus Bacillus are rich in PE (40-60%) and also have anionic lipids, PG (5-40%) and cardiolipin, CL (8-17%). Bacteria from Staphylococcus genus and most other Gram-positive bacteria lack PE, but instead have large amount of anionic phospholipids, PG (30-90%) and CL (up to 19%), which attribute a high negative charge to their membranes [64]. In bacterium E. fecalis, the negative charge of the cytoplasmic membrane is partially neutralized by the presence of 20% lysyl-PG, a cationic lipid, and 26% of phosphatidylkojibiosyl diglycerol, in uncharged lipid covalently bound to lipotechoic acid [65]. In contrast to archaeal membranes that keep liquid crystalline phase and low permeability at a wide range of temperatures, the permeability of bacterial fatty acid ester membranes is low only just above their phase-transition temperature and significantly increases at rising temperatures. This requires the existence of control mechanisms for temperature adaptation of bacteria, for example by regulating the lipid fatty acid iso/anteiso composition [61] or unsaturation level [66]. Cell membrane isolated from several Gram-positive bacteria (e.g. Baccilus) contain large amounts of proteins (53‐75%) and less lipid (20‐30%) [67].

membranes


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Archaebacterial cell membrane

Archaea are the most abundant microorganisms on the Earth that can thrive under extreme conditions [68, 69]. In contrast to bacteria and eukaryotes, whose membranes have sn-glycerol-3-phosphate backbone, ester linkages and fatty acid chains, archaeabacteria membranes are characterized by sn-glycerol-1-phosphate backbone, ether linkages, and isoprenoid hydrocarbon chains containing 20, 25 or 40 carbon atoms [70]. All halophiles and some methanoges have lipids based on archaeol (2,3,-di-phytanyl-sn-glycerol) with glycerol moiety linked to different polar head groups. In many methanogens and all thermophiles, membrane lipids are based on caldarchaeol (di-biphytanyl-diglycerol-tetraethers) with two long C40 chains that traverse the membrane core and have two polar head groups located at the opposing ends [71]. Polar lipids account for 80-90% of all membrane lipids, while the remainder are neutral squalenes and other isoprenoids [54].

Microorganisms that are able to thrive at extreme environmental conditions have developed a number of mechanisms of adaptation of their protein and membrane components. An essential feature of archaeal lipids is the low phase-transition temperature (between -20 and -15° C). This enable membranes to preserve the fluid liquid crystalline state over the wide temperature range (from 0° to 100° C), which is essential for optimal functioning of membrane proteins [61]. The presence of ether linkages, which are more heat resistant than ester linkages, enhance chemical stability of membrane lipids at high temperatures [72]. The C40 hydrocarbon chains of tetraether lipids span the entire membrane and stabilize it by linking the opposite leaflets. In thermophiles, the C40 isoprenoid moieties may have cyclopropane and cyclopentane rings, and the degree of cyclization is increasing at higher temperatures of the environment [70]. In the extremely thermophilic methanoarchaea (Methanocaldococcus jannaschii) the rise of the growth temperature leads to the increased ratio of caldarchaeol/cyclic archaeol/archaeol [73]. The adaptive traits of extreme haloalkaliphiles from the genus Natronococcus include synthesis of lipids with longer C25 isopropanoid chains and the enrichment in acidic lipids, such as ether cardiolipin [74].


Membrane structures.

Top: an archaeal phospholipid: 1, isoprene chains; 2, ether linkages; 3, L-glycerol moiety; 4, phosphate group.

Middle: a bacterial or eukaryotic phospholipid: 5, fatty acid chains; 6, ester linkages; 7, D-glycerol moiety; 8, phosphate group.

Bottom: 9, lipid bilayer of bacteria and eukaryotes; 10, lipid monolayer of some archaea.

All these adaptations results in more densely packed, more rigid, and stable membranes. At given temperature the membrane composed of tetraether lipids with saturated biphytanyl chains are more ordered and less flexible than phospholipid membranes [75]. The reduced segmental motion of methyl-branched phytanyl chains is regarded as a major cause of the low permeability of archaebacterial membranes to ions and solutes [72]. The cyclization of the chains in tetraether lipids may either decrease (cyclopropane and cyclopentane rings) or increase (cyclohexane rings) lipid motions and contributes to adequate membrane fluidity and low proton leakage rate at various temperatures [71, 72]. The increased membrane thickness due to the presence of long-chain lipids also decreases dissipation of a proton gradient across the membrane [74].

Archaea usually lack bacteria-type peptidoglicans that cover cell membranes, but some may have pseudo-peptidoglicans, chondroitin-like polymers, or an additional external layer of regularly arranged glycoproteins inserted into the outer leaflet of the membrane, so called crystalline surface layer (S-layer) [54, 76]. Negatively charged residues of surface glycoproteins may counteract with sodium ions, facilitate protein hydration, and prevent protein precipitation at increased salinity [69]. The coating of acidophiles by OH-rich sugar moieties of tetraether lipids may have a strong proton-sheltering effect preventing the proton from penetrating the cell membrane [77].

The adaptive features of proteins in hyperthermophilic archaea to heat stress involve the prevalence of smaller and mostly basic proteins with higher stability, as well as the enrichment of protein sequences by residues with larger volume and increased hydrophobicity, by aromatic residues (Trp, Tyr), and by charged residues that may form ionic bridges [68, 69, 78].


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