Abstract: Membrane proteins. Membrane proteins Functions of proteins in the cell membrane
The proportion of protein in the total mass of the membrane can vary within very wide limits - from 18% in myelin to 75% in the mitochondrial membrane.
Based on their location in the membrane, proteins can be divided into: integral And peripheral.
Integral proteins are generally hydrophobic and are easily incorporated into the lipid bilayer.
The interaction of such a protein with the membrane occurs in several stages. Protein first adsorbed on the surface of the bilayer, changes its conformation, establishing hydrophobic contact with the membrane. Then it happens insertion of protein into the bilayer. The depth of penetration depends on the strength of hydrophobic interaction and the ratio of hydrophobic and hydrophilic areas on the surface of the protein globule. Hydrophilic regions of the protein interact with the near-membrane layers on one or both sides of the membrane. Fixation of the protein globule in the membrane occurs due to electrostatic and hydrophobic interactions. The carbohydrate part of the protein molecules (if present) protrudes out. Due to their close connection with the bilayer, integral proteins have a significant impact on it: conformational rearrangements of the protein lead to a change in the state of the lipids, the so-called deformation of the bilayer.
Peripheral proteins have a shallower penetration depth into the lipid bilayer and, accordingly, interact more weakly with membrane lipids, having a much smaller effect on them than integral ones.
Based on the nature of their interaction with the membrane, proteins are divided into monotopic, bitopic, polytopic :
monotopic proteins interact with the membrane surface (mono - one of the lipid layers);
bitopic penetrate the membrane through (bi – two layers of lipids);
polytopic penetrate the membrane several times (poly-multiple interaction with lipids).
It is clear that the first belong to peripheral proteins, and the second and third to integral.
Membrane proteins can also be classified according to the function they perform. In this regard, structural proteins are isolated:
· proteins – enzymes;
· proteins – receptors;
transport proteins.
A special group consists of proteins of the cell cytoskeleton. Strictly speaking, these proteins are not components of the membrane, adjoining it from the cytoplasmic side. Cytoskeleton proteins are part of all its components: myofilaments contain actin protein molecules; microtubules contain the protein tubulin; intermediate filaments also contain a more polymorphic protein complex. The cytoskeleton not only provides elasticity of the membrane and resists changes in cell volume, but, apparently, is involved in various intra- and extracellular regulatory mechanisms.
Lipids in membranes are primarily responsible for their structural properties - they create a bilayer, or matrix, in which the active components of the membrane - proteins - are located. It is proteins that give various membranes their uniqueness and provide specific properties. Numerous membrane proteins perform the following main functions: they determine the transfer of substances across membranes (transport functions), carry out catalysis, provide the processes of photo- and oxidative phosphorylation, DNA replication, translation and modification of proteins, signal reception and transmission of nerve impulses, etc.
It is customary to divide membrane proteins into 2 groups: integral(internal) and peripheral(external). The criterion for such separation is the degree of strength of binding of the protein to the membrane and, accordingly, the degree of severity of processing necessary to extract the protein from the membrane. Thus, peripheral proteins can be released into solution even when membranes are washed with buffer mixtures with low ionic strength, low pH values in the presence of chelating substances, such as ethylenediaminetetraacetate (EDTA), which bind divalent cations. Peripheral proteins are released from membranes during such mild conditions, since they are associated with the heads of lipids or with other membrane proteins using weak electrostatic interactions, or with the help of hydrophobic interactions with the tails of lipids. On the contrary, integral proteins are amphiphilic molecules, have large hydrophobic regions on their surface and are located inside the membrane, so their extraction requires destruction of the bilayer. For these purposes, detergents or organic solvents are most often used. The methods for attaching proteins to the membrane are quite varied (Fig. 4.8).
Transport proteins. The lipid bilayer is an impermeable barrier to most water-soluble molecules and ions, and their transport across biomembranes depends on the activity of transport proteins. There are two main types of these proteins: channels(pores) and carriers. Channels are membrane-crossing tunnels in which binding sites for transported substances are accessible on both membrane surfaces simultaneously. Channels do not undergo any conformational changes during the transport of substances; their conformation changes only when opening and closing. Carriers, on the contrary, change their conformation during the transfer of substances across the membrane. Moreover, at any given time, the binding site of the transported substance in the carrier is accessible only on one surface of the membrane.
Channels, in turn, can be divided into two main groups: voltage-dependent and chemically regulated. An example of a potential-dependent channel is the Na + channel; its operation is regulated by changing the electric field voltage. In other words, these channels open and close in response to change transmembrane potential. Chemically regulated channels
open and close in response to the binding of specific chemical agents. For example, the nicotinic acetylcholine receptor, when a neurotransmitter binds to it, goes into an open conformation and allows monovalent cations to pass through (subsection 4.7 of this chapter). The terms “pore” and “channel” are usually used interchangeably, but pores are more often understood as non-selective structures that distinguish substances mainly by size and allow passage of all sufficiently small molecules. Channels are often understood as ion channels. The transport rate through the open channel reaches 10 6 - 10 8 ions per second.
Transporters can also be divided into 2 groups: passive and active. With the help of passive carriers, one type of substance is transported across the membrane. Passive transporters are involved in facilitated diffusion and only increase the flow of substances along an electrochemical gradient (for example, the transfer of glucose across erythrocyte membranes). Active carriers transport substances across the membrane using energy. These transport proteins accumulate substances on one side of the membrane, transporting them against the electrochemical gradient. The speed of transport using carriers depends very much on their type and ranges from 30 to 10 5 s -1. The terms “permease” and “translocase” are often used to designate individual transporters, which can be considered synonymous with the term “transporter”.
Enzyme functions of membrane proteins. A large number of different enzymes function in cell membranes. Some of them are localized in the membrane, finding there a suitable environment for the transformation of hydrophobic compounds, others, thanks to the participation of membranes, are located in them in strict order, catalyzing successive stages of vital processes, while others require the assistance of lipids to stabilize their conformation and maintain activity. Enzymes were found in biomembranes - representatives of all known classes. They can penetrate the membrane through, be present in it in dissolved form, or, being peripheral proteins, bind to membrane surfaces in response to any signal. The following can be distinguished characteristic types membrane enzymes:
1) transmembrane enzymes that catalyze coupled reactions on opposite sides of the membrane. These enzymes usually have several active centers located on opposite sides of the membrane. Typical representatives of such enzymes are components of the respiratory chain or photosynthetic redox centers that catalyze redox processes associated with electron transport and the creation of ion gradients on the membrane;
2) transmembrane enzymes involved in the transport of substances. Transport proteins that couple substance transfer with ATP hydrolysis, for example, have a catalytic function;
3) enzymes that catalyze the transformation of membrane-bound substrates. These enzymes are involved in the metabolism of membrane components: phospholipids, glycolipids, steroids, etc.
4) enzymes involved in the transformation of water-soluble substrates. With the help of membranes, most often in an attached state, enzymes can concentrate in those areas of the membrane where the content of their substrates is greatest. For example, enzymes that hydrolyze proteins and starch are attached to the membranes of intestinal microvilli, which helps to increase the rate of breakdown of these substrates.
Cytoskeletal proteins . The cytoskeleton is a complex network of protein fibers different types and is present only in eukaryotic cells. The cytoskeleton provides mechanical support for the plasma membrane and can determine the shape of the cell, as well as the location of organelles and their movement during mitosis. With the participation of the cytoskeleton, such important processes for the cell as endo- and exocytosis, phagocytosis, and amoeboid movement are also carried out. Thus, the cytoskeleton is the dynamic framework of the cell and determines its mechanics.
The cytoskeleton is formed from three types of fibers:
1) microfilaments(diameter ~6 nm). They are thread-like organelles - polymers of the globular protein actin and other proteins associated with it;
2) intermediate filaments (diameter 8-10 nm). Formed by keratins and related proteins;
3) microtubules(diameter ~ 23 nm) - long tubular structures.
They consist of a globular protein called tubulin, the subunits of which form a hollow cylinder. The length of microtubules can reach several micrometers in the cytoplasm of cells and several millimeters in the axons of nerves.
The listed cytoskeletal structures penetrate the cell in different directions and are closely associated with the membrane, attaching to it at some points. These sections of the membrane play an important role in intercellular contacts; with their help, cells can attach to the substrate. They also play an important role in the transmembrane distribution of lipids and proteins in membranes.
As a rule, it is proteins that are responsible for the functional activity of membranes. These include a variety of enzymes, transport proteins, receptors, channels, pores, etc. Previously, it was believed that membrane proteins have exclusively a β folded structure (the secondary structure of the protein), but these studies showed that membranes contain a large number of α helices. Further studies showed that membrane proteins can penetrate deeply into the lipid bilayer or even penetrate it and their stabilization is carried out due to hydrophobic...
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Lecture 5
Structure and functions of membrane proteins
Cell membranes contain protein from 20 to 80% (by weight). As a rule, it is proteins that are responsible for the functional activity of membranes. These include a variety of enzymes, transport proteins, receptors, channels, pores, etc. etc., which ensure the unique functions of each membrane. The first advances in the study of membrane proteins were achieved when biochemists learned to use detergents to isolate membrane proteins in a functionally active form. These were works on the study of enzyme complexes of the inner membrane of mitochondria. Previously, it was believed that membrane proteins have an exclusively β folded structure (protein secondary structure), but these studies showed that membranes contain a large number of α helices. The β helix is much less common, but it is, however, given important biological significance. The fact is that in areas surrounded by lipids, the β helix is a hollow cylinder, in the outer wall of which non-polar (hydrophobic) amino acid residues are concentrated, and in the inner hydrophilic ones. Such a cylinder could form a channel in the membrane through which ions and water-soluble substances freely pass. Further studies showed that membrane proteins can penetrate deeply into or even penetrate the lipid bilayer and are stabilized by hydrophobic interactions. There are at least four types of arrangement of proteins in membranes: The first type is transmembrane, when the protein penetrates the entire membrane, and the hydrophobic region of the protein has an α configuration. The bacteriorhodopsin molecule from Halobacterium halobium its α helices sequentially cross the bilayer; The second type is binding using a hydrophobic anchor, when the protein has a short region consisting of hydrophobic amino acid residues near the carboxyl end. This is the so-called hydrophobic anchor, which can be removed by proteolysis, and the released protein becomes water-soluble. This arrangement in the membrane is characteristic of many cytochromes. The third type is binding to the surface of the bilayer, when the interaction of proteins is primarily electrostatic in nature or hydrophobic in nature. This type of interaction can be used as an addition to other interactions, such as transmembrane anchoring. The fourth type is binding to proteins embedded in the bilayer, which is when some proteins bind to proteins that are located inside the lipid bilayer. For example, F 1 - part H + - ATPase that binds to F 0 the part immersed in the membrane, as well as some cytoskeletal proteins.
The basis of modern ideas about the structure of membrane proteins is the idea that their polypeptide chain is folded so as to form a nonpolar, hydrophobic surface in contact with the nonpolar region of the lipid bilayer. The polar domains of a protein molecule can interact with the polar heads of lipids on the surface of the bilayer. Many proteins are transmembrane and span the bilayer. Some proteins appear to be associated with the membrane only through their interaction with other proteins.
Many membrane proteins typically associate with the membrane through noncovalent interactions. However, there are proteins that are covalently linked to lipids. Many plasma membrane proteins belong to the class of glycoproteins. The carbohydrate residues of these proteins are always located on the outside of the plasma membrane.
Typically, membrane proteins are divided into external (peripheral) and internal (integral). In this case, the criterion is the degree of severity of the processing necessary to extract these proteins from the membrane. Peripheral proteins are released when membranes are washed with buffer solutions of low ionic strength, low or, conversely, high pH and in the presence of chelating agents (for example, EDTA) that bind divalent cations. It is often very difficult to distinguish peripheral membrane proteins from proteins bound to the membrane during the release process.
To release integral membrane proteins, it is necessary to use detergents or even organic solvents.
Many eukaryotic and prokaryotic membrane proteins are covalently linked to lipids, which are added to the polypeptide after translation.
Membrane proteins covalently associated with lipids
(A) Proteins to which myristic acid is attached
(B) Proteins to which palmitic acid is attached
(IN) Proteins with glycosylphosphatidylinositol anchor
4. Nerve cell adhesion molecule |
In some cases, these lipids play the role of a hydrophobic anchor, with the help of which the protein is attached to the membrane. In other cases, lipids are likely to act as an aid in protein migration to the appropriate cell region or (as in the case of viral envelope proteins) in membrane fusion.
In prokaryotes, the most fully characterized protein is Brown's lipoprotein, the main lipoprotein of the outer membrane. E. coli . The mature form of this protein contains acylglycerol, which is linked by a thioether bond to N terminal cysteine. Besides, N The terminal amino acid is linked to the fatty acid by an amide bond. The membrane-bound form of penicillase is attached to the cytoplasmic membrane by N terminal acylglycerol similar to membrane lipoproteins.
Membrane proteins of eukaryotes are covalently associated with lipids, as shown in the table, they can be divided into three classes. Proteins of the first two classes appear to be localized mainly on the cytoplasmic surface of the plasma membrane, and proteins of the third class on the outer surface.
There are membrane proteins that are covalently linked to carbohydrates. These include cell surface proteins mainly performing the functions of transport and reception. It's still unclear what's going on here. This may be due to the fact that proteins need to be sorted when directed towards the plasma membrane. Sugar residues may protect the protein from proteolysis or participate in recognition or adhesion. Therefore, sugar residues in membrane glycoproteins are localized exclusively on the outer side of the membrane.
Two main classes of oligosaccharide structures of membrane glycoproteins can be distinguished: 1) N glycosidic oligosaccharides linked to proteins through the amide group of aspargine; 2) O-glycosidic oligosaccharides linked through the hydroxyl groups of serine and threonine. This class of oligosaccharides consists of three subclasses.
- A simple or mannose-rich complex in which the oligosaccharide contains mannose and N acetylglucosamine.
- A normal complex in which the mannose-rich core has additional side branches containing other saccharide residues, such as sialic acid.
- Large complex that is associated with the anionic transporter of the erythrocyte membrane
Most membrane glycoprotein oligosaccharides belong to subclass 1 or 2.
Membrane proteins of bacteria
As noted above, proteins in the cytoplasmic membrane make up about 50% of its surface. Approximately 10% of the membrane is formed by tightly bound protein-lipid complexes. The molecule of any protein embedded in the membrane is surrounded by 45 × 130 or more lipid molecules. About half of the free lipids are associated with peripheral membrane proteins.
The protein composition of the cytoplasmic membrane of bacteria is more diverse than the lipid composition. Thus, in the cytoplasmic membrane E. coli K 12 About 120 different proteins have been discovered. Depending on the orientation in the membrane and the nature of the connection with the lipid bilayer, as noted above, proteins are divided into integral and peripheral. Peripheral bacterial proteins include a number of enzymes such as NADH dehydrogenase, malate dehydrogenase, etc., as well as some proteins that are part of the ATPase complex. This complex is a group of protein subunits arranged in a certain way, in contact with the cytoplasm, periplasmic space and forming a channel in the membrane through which the proton passes. The area of the complex designated F 1 , immersed in the cytoplasm, and and with components of the site F 0 The hydrophobic sides of the molecules are immersed in the membrane. Subunit b partially immersed in the membrane with its hydrophobic part and communicates the membrane and cytoplasmic parts of the enzyme complex, as well as the connection of ATP synthesis in the region F 1 with proton potential in the membrane. Subunits a, b and c provide a proton channel. Other components of the complex ensure its structural and functional integrity.
Towards integral proteins E. coli, which require lipids for the manifestation of enzymatic activity, include succinate dehydrogenase, cytochrome b . Very interesting properties has the antibiotics gramicidin A, alamethicin, amphotericin and nystacin. When they interact with the bacterial membrane, they become integral proteins (antibiotics are polypeptides and macrocycles).
Gramicidin A is a hydrophobic peptide consisting of 15 L-D -amino acids. When embedded in a membrane, it forms channels that allow monovalent cations to pass through. This channel, which forms gramicidin A, has been most fully characterized. The channel is formed by two molecules of gramicidin A. As a result of alternation L- and D - amino acids form a helix in which the side chains are located outside, and the carboxyl groups of the backbone are inside the channel. This type of helix is not found in any other proteins and is formed from the unusual alternation of stereoisomers of amino acids in gramicidin A. The gramicidin channel, as noted above, is cation-selective. Small inorganic and organic cations pass through it, at the same time permeability through Cl - is equal to zero.
Alamethicin is a peptide antibiotic of 20 amino acid residues, capable of forming electrically excitable channels in the membrane. The amino acid sequence of alamethicin includes the unusual residues α aminobutyric acid and L phenylalanine. When bound to a membrane, unlike gramicidin A, it forms a pore. It is much smaller in size than the channel that forms gramicidin A. This is primarily due to the fact that the space around the α helix is too small for an ion to pass through.
Marcolide antibiotics such as nystatin and amphotericin bind to cholesterol and form channels. The channels form 8 × 10 molecules of these polyene antibiotics, through which, however, ions penetrate at low rates.
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TO membrane proteins These include proteins that are embedded in or associated with the cell membrane or the membrane of a cell organelle. About 25% of all proteins are membrane proteins.
Biochemical classification
According to the biochemical classification, membrane proteins are divided into integral And peripheral.
- Integral membrane proteins firmly embedded in the membrane and can be removed from the lipid environment only with the help of detergents or non-polar solvents. In relation to the lipid bilayer, integral proteins can be transmembrane polytopic or integral monotopic.
- Peripheral membrane proteins are monotopic proteins. They are either weakly bound to the lipid membrane or associate with integral proteins due to hydrophobic, electrostatic or other non-covalent forces. Thus, unlike integral proteins, they dissociate from the membrane when treated with an appropriate aqueous solution (eg, low or high pH, high salt concentration, or a chaotropic agent). This dissociation does not require membrane disruption.
Membrane proteins can be integrated into the membrane due to fatty acid or prenyl residues or glycosylphosphatidylinositol attached to the protein during their post-translational modification.
Another important point is the ways proteins attach to the membrane:
1. Binding with proteins immersed in the bilayer. Examples include the F1 part of H + - ATPase, which binds to the Fo part immersed in the membrane; Some cytoskeletal proteins may also be mentioned.
2. Binding to the bilayer surface. This interaction is primarily electrostatic in nature (eg, myelin basic protein) or hydrophobic (eg, surfactant peptides and possibly phospholipases). On the surface of some membrane proteins there are hydrophobic domains formed due to the characteristics of the secondary or tertiary structure. These surface interactions can be used in addition to other interactions, such as transmembrane anchoring.
3. Binding using a hydrophobic “anchor”; this structure is usually revealed as a sequence of non-polar amino acid residues (for example, in cytochrome 65). Some membrane proteins use covalently bound fatty acids or phospholipids as anchors.
4. Transmembrane proteins. Some of them cross the membrane only once (for example, glycophorin), others - several times (for example, lactose permease; bacteriorhodopsin).
Membrane lipids
Membrane lipids are amphipathic molecules that spontaneously form bilayers. Lipids are insoluble in water, but readily dissolve in organic solvents. In most animal cells they make up about 50% of the mass of the plasma membrane. In a region of the lipid bilayer measuring 1 x 1 µm there are approximately 5 x 1OO thousand lipid molecules. Therefore, the plasma membrane of a small animal cell contains approximately 10 lipid molecules. There are three main types of lipids in the cell membrane:
1) phospholipids (the most common type); complex lipids containing glycerol, fatty acids, phosphoric acid and a nitrogenous compound.
A typical phospholipid molecule has a polar head and two hydrophobic hydrocarbon tails. The length of the tails varies from 14 to 24 carbon atoms in the chain. One of the tails typically contains one or more cis double bonds (an unsaturated hydrocarbon), while the other (a saturated hydrocarbon) has no double bonds. Each double bond causes a bend in the tail. Such differences in tail length and hydrocarbon chain saturation are important because they affect membrane fluidity.
Amphipathic molecules in an aqueous environment tend to aggregate, with the hydrophobic tails being hidden and the hydrophilic heads remaining in contact with the water molecules. This type of aggregation occurs in two ways: either by the formation of spherical micelles with tails facing inward, or by the formation of bimolecular films, or bilayers, in which the hydrophobic tails are located between two layers of hydrophilic heads.
The two main phospholipids that are present in plasma are phosphatidylcholine (lecithin) and sphingomyelin. Phospholipid synthesis occurs in almost all tissues, but the main source of plasma phospholipids is the liver. The small intestine also supplies phospholipids, namely lecithin, in the composition of chylomicrons into the plasma. Most of phospholipids that enter the small intestine (including in the form of complexes with bile acids) undergo preliminary hydrolysis by pancreatic lipase. This explains why polyunsaturated lecithin added to food does not affect plasma phospholipid linoleate content any more than equivalent amounts of corn oil triglycerides.
Phospholipids are an integral component of all cell membranes. There is a constant exchange of phosphatidylcholine and sphingomyelin between plasma and red blood cells. Both of these phospholipids are present in plasma as constituents of lipoproteins, where they play a key role in maintaining the soluble state of nonpolar lipids such as triglycerides and cholesteryl esters. This property reflects the amphipathic nature of phospholipid molecules - non-polar chains of fatty acids are able to interact with the lipid environment, and polar heads - with the aqueous environment (Jackson R.L. ea, 1974).
2) Cholesterol. Cholesterol is a sterol containing a four-ring steroid core and a hydroxyl group.
This compound is found in the body both as a free sterol and as an ester with one of the long-chain fatty acids. Free cholesterol is a component of all cell membranes and is the main form in which cholesterol is present in most tissues. The exception is the adrenal cortex, plasma and atheromatous plaques, where cholesterol esters predominate. In addition, a significant part of the cholesterol in the intestinal lymph and in the liver is also esterified.
Cholesterol is contained in lipoproteins either in free form or in the form of esters with long-chain fatty acids. It is synthesized in many tissues from acetyl-CoA and excreted from the body by bile in the form of free cholesterol or bile salts. Cholesterol is a precursor to other steroids, namely corticosteroids, sex hormones, bile acids and vitamin D. It is a compound typical of animal metabolism and is found in significant quantities in animal products: egg yolk, meat, liver and brain.
The plasma membranes of eukaryotes contain fairly large amounts of cholesterol—approximately one molecule for every phospholipid molecule. In addition to regulating fluidity, cholesterol increases the mechanical strength of the bilayer. Cholesterol molecules are oriented in the bilayer in such a way that their hydroxyl groups are adjacent to the polar heads of phospholipid molecules
3) glycolipids
Glycolipids are lipid molecules belonging to the class of oligosaccharide-containing lipids that are found only in the outer half of the bilayer and their sugar groups are oriented toward the cell surface.
Glycolipids are sphingolipids in which a FA residue is attached to the NH group of sphingazine, and the following groups are attached to the oxygen of sphingazine: oligosaccharide chains, Gal, Glc, GalNAc (neuraminic acid) - gangliosides. Gal or Glc are cerebrosides. sulfosaccharides Glc-SO3H, Gal-SO3H – sulfolipids.
Glycolipids are found on the surface of all plasma membranes, but their function is unknown. Glycolipids make up 5% of the lipid molecules of the outer monolayer and vary greatly among different types and even in different tissues of the same species. In animal cells they are synthesized from sphingosine, a long amino alcohol, and are called glycosphingolipids.
Their structure is generally similar to the structure of phospholipids formed from glycerol. All glycolipid molecules differ in the number of sugar residues in their polar heads. One of the simplest glycolipids is galactocerebroside.
Membrane phospholipids act as a solvent for membrane proteins, creating a microenvironment in which the latter can function. Of the 20 amino acids that make up proteins, six are highly hydrophobic due to the side groups attached to the a-carbon atom, several amino acids are slightly hydrophobic, and the rest are hydrophilic. As we saw in Chap. 5, when an α-helix is formed, the hydrophobicity of the peptide groups themselves is minimized. In this way, proteins can form an integral whole with the membrane. To do this, it is necessary that their hydrophilic sections protrude from the membrane into the cell and out, and their hydrophobic sections penetrate the hydrophobic core of the bilayer. Indeed, those sections of protein molecules that are immersed in the membrane contain a large number of hydrophobic amino acids and are characterized by a high content of α-helices or β-sheets.
Table 42.2. Enzyme markers of various membranes
The number of different proteins in the membrane varies from 6-8 in the sarcoplasmic reticulum to more than 100 in the plasma membrane. These are enzymes, transport proteins, structural proteins, antigens (i.e. proteins that determine histocompatibility) and receptors for various molecules. Since each membrane is characterized by its own set of proteins, it is impossible to talk about the existence of a certain typical membrane structure. In table 42.2 shows the enzymatic activities inherent in some types of membranes.
Membranes are dynamic structures. Membrane proteins and lipids are constantly renewed. The renewal rates of different lipids, as well as different proteins, vary over a wide range. The membranes themselves can renew themselves even faster than any of their components. This issue will be discussed in more detail in the section on endocytosis.
Membrane asymmetry
Asymmetry is important property membranes and, apparently, is partly due to the uneven distribution of proteins in the membrane. Transmembrane asymmetry may also be due to different localization of carbohydrates associated with membrane proteins. In addition, some specific enzymes may be located on the outer or inner side of the membrane; this applies to both mitochondrial and plasma membranes.
Membranes also have local asymmetry. In some cases (for example, in the brush border of mucosal cells) it appears almost at a macroscopic level. In other cases (for example, in the region of gap junctions, tight junctions and synapses that occupy a very small part of the membrane area), the areas of local asymmetry are small.
There is also an asymmetry in the distribution of phospholipids between the outer and inner sides of the membranes (transverse asymmetry). Thus, choline-containing phospholipids (phosphatidylcholine and sphingomyelin) are located mainly in the outer molecular layer, and aminophospholipids
(phosphatidylserine and phosphatidylethanolamine) - mainly in the internal. Cholesterol is usually found in the outer layer of large quantities than in the internal one. It is obvious that if such asymmetry exists in principle, then the transverse mobility (flip-flop) of membrane phospholipids should be limited. Indeed, phospholipids in synthetic bilayers are characterized by extremely low jump rates—the lifetime of the asymmetry can be measured in days or weeks. However, with the artificial inclusion of certain membrane proteins, for example the erythrocyte protein glycophorin, into synthetic bilayers, the frequency of phospholipid flip-flop transitions can increase a hundred times.
The mechanisms of asymmetric lipid distribution have not yet been established. The enzymes involved in the synthesis of phospholipids are localized on the cytoplasmic side of the membranes of microsomal vesicles. Thus, it can be assumed that there are translocases that transfer certain phospholipids from the inner layer to the outer one. In addition, specific proteins may be present in both layers, preferentially binding certain phospholipids and leading to their asymmetric distribution.
Integral and peripheral membrane proteins
Most membrane proteins are integral components of membranes (they interact with phospholipids); Almost all sufficiently fully studied proteins have a length exceeding 5-10 nm, a value equal to the thickness of the bilayer. These integral proteins are usually globular amphiphilic structures. Both of their ends are hydrophilic, and the region that crosses the core of the bilayer is hydrophobic. After establishing the structure of integral membrane proteins, it became clear that some of them (for example, carrier protein molecules) can cross the bilayer multiple times, as shown in Fig. 42.7.
Integral proteins are distributed asymmetrically in the bilayer (Fig. 42.8). If a membrane containing asymmetrically distributed integral proteins is dissolved in detergent and then the detergent is slowly removed, self-organization of phospholipids and integral proteins will occur and a membrane structure will be formed, but the proteins in it will no longer be specifically oriented. Thus, the asymmetric orientation in the membrane of at least some proteins can be determined when they are included in the lipid bilayer. The outer hydrophilic part of the amphiphilic protein, which of course is synthesized inside the cell, must then cross the hydrophobic layer of the membrane and ultimately end up on the outside.
Rice. 42.7. A proposed model of a glucose transporter in humans. The transporter is assumed to cross the membrane 12 times. Membrane-crossing regions can form amphiphilic α-helices with amide and hydroxyl side groups and appear to bind glucose or form a channel for its transport. The amino and carboxyl ends of the chain are located on the cytoplasmic surface. (From Mueckler et al.: Sequence and structure of a human glucose transporter. Science, 1985. 229, 941, with kind permission.)
We will discuss the molecular mechanisms of membrane organization later.
Peripheral proteins do not interact directly with phospholipids in the bilayer; instead, they form weak bonds with the hydrophilic regions of specific integral proteins. For example, ankyrin, a peripheral protein, is associated with the integral protein of band III of the erythrocyte membrane. Spectrin, which forms the skeleton of the erythrocyte membrane, is in turn associated with ankyrin and thus plays an important role in maintaining the biconcave shape of the erythrocyte. Immunoglobulin molecules are integral proteins of the plasma membrane and are released only along with a small fragment of the membrane. Many receptors for various hormones are integral proteins, and the specific polypeptide hormones that bind to these receptors can thus be considered peripheral proteins. Such peripheral proteins as peptide hormones can even determine the distribution of integral proteins - their receptors - in the plane of the bilayer (see below).
