transmembrane receptors. transmembrane protein end product of transmembrane proteins

: characteristics and structural principles

1. Structure of membrane proteins

The main role of lipids in membranes is to stabilize the bilayer structure, while proteins are active components of biomembranes. We will discuss some of the principles that have proven useful in elucidating the structural features of membrane proteins. We will give examples illustrating these principles.

At the dawn of the development of membranology, it was believed that membrane proteins were rather homogeneous in their structure and stacked in the form of 3-layers on the surface of the bilayer. Today, it is more likely that they are inclined to believe that, at least in transmembrane proteins, those parts of them that are immersed in the membrane contain a-helices. Of course, I would very much like to draw some unambiguous conclusions about this, but they must be based on actual data. In the face of the enormous structural diversity of soluble proteins, one comes to the conclusion that integral membrane proteins may be much more complex than we now imagine. The classification of soluble proteins into structure types was carried out only after the structure of more than 100 different proteins had been established with high resolution. As for transmembrane proteins, this was done only in one case - for the protein of the photosynthetic reaction center of bacteria. Together with low resolution electron microscopy data on the structure of bacteriorhodopsin, this is the only source on which model building for most other transmembrane proteins can be based.

Another important point is the methods of attaching proteins to the membrane. They are shown schematically in Fig. 3.1.

1. Binding to proteins immersed in the bilayer. Examples include the Fi part of H+-ATPase, which binds to the Fo part embedded in the membrane; some cytoskeletal proteins can also be mentioned.

2. Binding to the bilayer surface. This interaction is primarily electrostatic or hydrophobic in nature. On the surface of some membrane proteins there are hydrophobic domains that are formed due to the features of the secondary or tertiary structure. These surface interactions can be used in addition to other interactions such as transmembrane anchoring.

3. Binding with a hydrophobic "anchor"; this structure usually comes to light as a sequence of non-polar amino acid residues. Some membrane proteins use covalently bound fatty acids or phospholipids as anchors.

4. Transmembrane proteins. Some of them cross the membrane only once, others - several times.

Differences between outer and inner membrane proteins do not unambiguously specify the mode of their attachment to the bilayer; these differences determine only the relative strength of their binding.

2. Purification of membrane proteins

To purify integral membrane proteins and obtain them in a biochemically active form, detergents are needed to solubilize proteins and keep them in solution. Detergent requirements and handling pose additional challenges beyond those commonly encountered in protein purification. Many specific methods have been developed for the isolation of integral membrane proteins, but most purification schemes are based on the same chromatographic and hydrodynamic techniques that are used for soluble proteins. These are chromatography on DEAE-cellulose, sepharose or hydroxylapatite, gel filtration, centrifugation in a sucrose density gradient, etc. The right choice of detergent is very important, since it is the detergent that destroys the biomembrane, taking the place of lipids surrounding a particular protein, and determines the stability of a protein in solution. The mechanisms of action of detergents are considered in the review.

2.1. DETERGENTS

During the last two decades, a lot of detergents have appeared that are suitable for the purification of integral membrane proteins. In principle, one should try to find a detergent that would not disrupt the secondary and tertiary structures of membrane proteins, but would only replace most or all of the membrane lipids in contact with the hydrophobic regions of the protein molecule. The ultimate goal of solubilization is the incorporation of the protein into the detergent micelle; a subsequent purification strategy is to separate such protein-detergent complexes.

The first problem is the selection of optimal solubilization conditions for the studied protein. Detergents that denature proteins are not suitable for such a delicate task. On the other hand, many detergents are not efficient enough to destroy membranes and form protein-containing mixed micelles. Such detergents may be either too hydrophobic or too hydrophilic to mix effectively with membrane lipids and, at high enough concentrations, to convert the bilayer into globular mixed micelles. At first, it was hoped that the choice of the required detergent could be systematized using one parameter, called the hydrophilic-lipophilic balance. This parameter, ranging from 1 to 20, is used in the production of surfactants as a measure of relative hydrophobicity. Indeed, some correlations have been obtained, from which it follows that the HLB value of a detergent can be used to predict its behavior in biological systems. Generally speaking, detergents with an HLB value in the range of 12.5 to 14.5 can be said to be the most effective solvents for integral membrane proteins. However, later it turned out that the search for optimal detergents for a particular membrane protein requires taking into account many factors and should always be accompanied by empirical verification. The following must be taken into account.

1.Maximum solubilization of the studied protein. The criterion is the transition of the protein into the supernatant after centrifugation, during which the membrane is precipitated.

2. Solubilization of the protein in the desired form. Usually we are talking about the preservation of its enzymatic activity, but sometimes certain spectral characteristics or the presence of specific protein associates are used. In addition, a necessary condition is the stability of the protein after solubilization. In some cases, exogenous phospholipids are added along with the detergent to maintain biochemical activity. An example is the production of E. coli lactose permease and sodium channel protein. Glycerol or another polyol is sometimes added to stabilize the protein after solubilization. It makes sense to also use protease inhibitors and carry out solubilization under conditions that minimize the likelihood of their proteolytic cleavage.

3. The possibility of using a detergent in this technique. First of all, it is necessary to take into account the charge of the detergent, the behavior at a given pH value, the CMC and the size of the detergent micelles. The last properties are especially important. Detergents with low CMC, which form large micelles, are not removed by dialysis or ultrafiltration due to too low a concentration of detergent monomers. From a practical point of view, this means that if the protein is concentrated by ultrafiltration, the concentration of the low CMC detergent will also increase, and this can lead to protein denaturation. For this reason, many researchers prefer to use detergents with high CMCs, such as octylglucoside, bile salts, or more recent zwitterionic detergents. Polystyrene resins such as Biobids SM-2 are very valuable. They selectively bind to detergents such as Triton X-100, remove them from the solution and make it possible to dispense with dialysis altogether. Another factor to consider is the absorption of light by the detergent. Some detergents, such as Triton X-100, absorb in the near UV region, making it impossible to determine protein concentration by measuring optical density at a wavelength of 280 nm.

Taking into account all these factors, it becomes clear why in many cases the isolation of integral membrane proteins requires the use of different detergents. For example, Triton X-100 can be used for solubilization, and separation with DEAE-cellulose is best done in the presence of octylglucoside. Detergents can be changed during the chromatography step, during density gradient centrifugation, and in some cases by dialysis. It should be borne in mind that a detergent unsuitable for solubilizing a particular protein can be very effective in keeping the protein in solution after detergent change. Cleaning should almost always be carried out with an excess of detergent in the solution, otherwise the equilibrium will be shifted towards the aggregation of membrane proteins, and not towards the formation of protein-detergent complexes. In some cases, such aggregation may even be desirable, and the last purification step may be to remove the detergent. But, as a rule, with a lack of detergent, irreversible precipitation and protein loss occur.

The need to maintain the detergent concentration at a certain level creates additional difficulties beyond those usually encountered in the purification of proteins; we have already talked about some of them. Problems also arise when using the standard salting out method at a high concentration of ammonium sulfate: in many cases, the protein is precipitated in combination with the detergent and lipid. Because the brine has a high density and the detergent in the aggregate is relatively low, a precipitate will remain on the surface during centrifugation. It is important to remember that protein-detergent complexes are subjected to purification, often with a significant amount of bound phospholipid. This affects the quality of separation during chromatography, as well as the results of characterization of the final prosoluble proteins, it is necessary to determine the number and molecular weight of polypeptide subunits, their stoichiometry, size and, possibly, the shape of the molecule, and, if necessary, biochemical activity.

Lipids in the composition of membranes are assigned, first of all, 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 processes of photo- and oxidative phosphorylation, DNA replication, translation and modification of proteins, signal reception and transmission of a nerve impulse, etc.

It is customary to divide membrane proteins into 2 groups: integral(internal) and peripheral(external). The criterion for such a separation is the degree of strength of protein binding to the membrane and, accordingly, the degree of processing severity required to extract the protein from the membrane. Thus, peripheral proteins can be released into solution already when membranes are washed with buffer mixtures with low ionic strength, low pH values in the presence of chelating agents, for example, ethylenediaminotetraacetate (EDTA), which bind divalent cations. Peripheral proteins are released from membranes under such mild conditions, since they are associated with lipid heads or with other membrane proteins by weak electrostatic interactions, or by hydrophobic interactions with lipid tails. On the contrary, integral proteins are amphiphilic molecules, have large hydrophobic regions on their surface, and are located inside the membrane; therefore, to extract them, it is necessary to destroy the bilayer. For these purposes, detergents or organic solvents are most often used. The ways of attaching proteins to the membrane are quite diverse (Fig. 4.8).

Transport proteins. The lipid bilayer is an impenetrable barrier for most water-soluble molecules and ions, and their transport through 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 the binding sites of the transported substances are available on both surfaces of the membrane at the same time. 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 each specific point in time, the binding site of the transferred substance in the carrier is available 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 voltage-dependent channel is the Na + channel, its operation is regulated by a change in the electric field voltage. In other words, these channels open and close in response to a change transmembrane potential. Chemically regulated channels

open and close in response to the binding of specific chemical agents. For example, when a neurotransmitter binds to the nicotinic acetylcholine receptor, it changes into an open conformation and allows monovalent cations to pass through (subsection 4.7 of this chapter). The terms "pore" and "channel" are usually interchangeable, but sometimes they are understood as non-selective structures that distinguish substances mainly by size and allow all sufficiently small molecules to pass through. Channels are often referred to as ion channels. The rate of transport through an open channel reaches 10 6 - 10 8 ions per second.

Carriers can also be divided into 2 groups: passive and active. With the help of passive carriers, one type of substances is transported across the membrane. Passive carriers are involved in facilitated diffusion and only increase the flow of the substance, carried out along the electrochemical gradient (for example, the transfer of glucose through the membranes of erythrocytes). Active carriers transport substances across the membrane at the cost of energy. These transport proteins accumulate substances on one side of the membrane, carrying them against the electrochemical gradient. The speed of transport with the help of carriers depends very much on their type and ranges from 30 to 10 5 s -1 . Often, the terms "permease", "translocase" are used to refer to individual carriers, which can be considered synonymous with the term "carrier".

Enzymatic functions of membrane proteins. A wide variety of enzymes function in cell membranes. Some of them are localized in the membrane, finding there a suitable environment for the conversion of hydrophobic compounds, others, due to the participation of membranes, are located in them in strict order, catalyzing successive stages of vital processes, and others need 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 a dissolved form, or, being peripheral proteins, bind to membrane surfaces in response to some signal. The following characteristic types of membrane enzymes can be distinguished:

1) transmembrane enzymes that catalyze coupled reactions on opposite sides of the membrane. These enzymes have, as a rule, several active centers located on opposite sides of the membrane. Typical representatives of such enzymes are respiratory chain components or photosynthetic redox centers that catalyze redox processes associated with electron transport and the creation of ionic gradients on the membrane;

2) transmembrane enzymes involved in the transport of substances. Transport proteins that couple the transfer of a substance with ATP hydrolysis, for example, have a catalytic function;

3) enzymes that catalyze the conversion 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 the state attached to them, enzymes can concentrate in those areas of the membranes where the content of their substrates is greatest. For example, enzymes that hydrolyze proteins and starch attach to the membranes of intestinal microvilli, which increases the rate of degradation of these substrates.

Proteins of the cytoskeleton . The cytoskeleton is a complex network of protein fibers of various types and is present only in eukaryotic cells. The cytoskeleton provides mechanical support for the plasma membrane, 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 filamentous 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 the globular protein 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.

These structures of the cytoskeleton 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.

Proteins Associated with Polar Heads of Membrane Lipids

Proteins that form complexes with integral membrane proteins

Surface proteins

Surface proteins often attach to the membrane by interacting with integral proteins or surface regions of the lipid layer.

A number of digestive enzymes involved in the hydrolysis of starch and proteins are attached to the integral proteins of the intestinal microvilli membranes.

Examples of such complexes are sucrase-isomaltase and maltase-glycoamylase. It is possible that the association of these digestive enzymes with the membrane makes it possible to hydrolyze the substrates at a high rate and assimilate the products of hydrolysis by the cell.

Polar or charged domains of a protein molecule can interact with the polar "heads" of lipids, forming ionic and hydrogen bonds. In addition, many proteins soluble in the cytosol can, under certain conditions, bind to the membrane surface for a short time. Sometimes protein binding is a necessary condition for the manifestation of enzymatic activity. Such proteins, for example, include protein kinase C, blood coagulation factors.

Anchoring with a membrane "anchor"

An "anchor" can be a non-polar domain of the protein, built from amino acids with hydrophobic radicals. An example of such a protein is cytochrome b 5 of the ER membrane. This protein is involved in redox reactions as an electron carrier.

The role of the membrane "anchor" can also be performed by a fatty acid residue covalently bound to the protein (myristic - C 14 or palmitic - C 16). Proteins associated with fatty acids are localized mainly on the inner surface of the plasma membrane. Myristic acid adds to the N-terminal glycine to form an amide bond. Palmitic acid forms a thioether bond with cysteine or an ester bond with serine and threonine residues.

A small group of proteins can interact with the outer surface of the cell using a phosphatidylinositolglycan covalently attached to the C-terminus of the protein. This "anchor" is often the only link between the protein and the membrane, therefore, under the action of phospholipase C, this protein is separated from the membrane.

Some of the transmembrane proteins penetrate the membrane once (glycophorin), others have several sections (domains) that successively cross the bilayer.

Integral membrane proteins containing from 1 to 12 transmembrane domains. 1- LDL receptor; 2 - GLUT-1 - glucose transporter; 3 - insulin receptor; 4 - adrenoreceptor.

The transmembrane domains spanning the bilayer have an α-helix conformation. Polar amino acid residues face inside the globule, while non-polar ones contact with membrane lipids. Such proteins are called "inverted" in comparison with water-soluble proteins, in which most of the hydrophobic amino acid residues are hidden inside, and the hydrophilic ones are located on the surface.

biological membranes located on the border of the cell and the extracellular space, as well as on the border of the membrane organelles of the cell (mitochondria, endoplasmic reticulum, Golgi complex, lysosomes, peroxisomes, nucleus, membrane vesicles) and the cytosol are essential for the functioning of both the cell as a whole and its organelles. Cell membranes have a fundamentally similar molecular organization. In this chapter, biological membranes are considered mainly on the example of the plasma membrane (plasmolemma), which delimits the cell from the extracellular environment.

Any biological membrane(Fig. 2–1) consists of phospholipids(~50%) and proteins (up to 40%). In smaller quantities, the membrane contains other lipids, cholesterol and carbohydrates.

Rice. 2–1. consists of a double layer phospholipids, the hydrophilic parts of which (heads) are directed to the membrane surface, and the hydrophobic parts (tails that stabilize the membrane in the form of a bilayer) inside the membrane. I - integral proteins embedded in the membrane. T - transmembrane proteins permeate the entire thickness of the membrane. P - peripheral proteins located either on the outer or inner surface of the membrane.

Phospholipids. The phospholipid molecule consists of a polar (hydrophilic) part (head) and an apolar (hydrophobic) double hydrocarbon tail. In the aqueous phase, phospholipid molecules automatically aggregate tail to tail, forming the framework of a biological membrane (Figs. 2–1 and 2–2) in the form of a double layer (bilayer). Thus, in the membrane, the tails of phospholipids (fatty acids) are directed inside the bilayer, and the heads containing phosphate groups are turned outward.

Arachidonic acid. From membrane phospholipids, arachidonic acid is released - a precursor of Pg, thromboxanes, leukotrienes and a number of other biologically active substances with many functions (inflammatory mediators, vasoactive factors, second mediators, etc.).

Liposomes- Membrane vesicles artificially prepared from phospholipids with a diameter of 25 nm to 1 μm. Liposomes used as models of biological membranes, as well as for introducing various substances into the cell (for example, genes, drugs); the latter circumstance is based on the fact that membrane structures (including liposomes) fuse easily (due to the phospholipid bilayer).

Squirrels biological membranes are divided into integral (including transmembrane) and peripheral (Fig. 2-1 and 2-2).

Integral membrane proteins (globular) are embedded in the lipid bilayer. Their hydrophilic amino acids interact with the phosphate groups of phospholipids, while their hydrophobic amino acids interact with fatty acid chains. Integral membrane proteins include adhesion proteins, some receptor proteins (membrane receptors).

transmembrane protein - a protein molecule that passes through the entire thickness of the membrane and protrudes from it both on the outer and on the inner surface. Transmembrane proteins include pores, ion channels, transporters, pumps, and some receptor proteins.

Pores and channels- transmembrane pathways, along which water, ions and metabolite molecules move between the cytosol and the intercellular space (and in the opposite direction).

carriers carry out transmembrane movement of specific molecules (including in combination with the transfer of ions or molecules of another type).

Pumps move ions against their concentration and energy gradients (electrochemical gradient) using the energy released during ATP hydrolysis.

Peripheral membrane proteins (fibrillar and globular) are located on one of the surfaces of the cell membrane (outer or inner) and are non-covalently associated with integral membrane proteins.

Examples of peripheral membrane proteins associated with the outer surface of the membrane - receptor proteins And adhesion proteins.

Examples of peripheral membrane proteins associated with the inner surface of the membrane are - cytoskeletal proteins, proteins of the second messenger system, enzymes and other proteins.

lateral mobility. Integral proteins can be redistributed in the membrane as a result of interaction with peripheral proteins, elements of the cytoskeleton, molecules in the membrane of neighboring cells, and components of the extracellular matrix.

Carbohydrates(mainly oligosaccharides) are part of the glycoproteins and glycolipids of the membrane, accounting for 2–10% of its mass (Fig. 2–2). Lectins interact with cell surface carbohydrates. Chains of oligosaccharides protrude on the outer surface of cell membranes and form a surface shell - glycocalyx.

Glycocalyx has a thickness of about 50 nm and consists of oligosaccharides covalently associated with glycoproteins and glycolipids of the plasma membrane. Functions of the glycocalyx: intercellular recognition, intercellular interactions, parietal digestion (the glycocalyx covering the microvilli of the border cells of the intestinal epithelium contains peptidases and glycosidases that complete the breakdown of proteins and carbohydrates).

Membrane permeability

The membrane bilayer separates the two aqueous phases. So, the plasma membrane separates the intercellular (interstitial) fluid from the cytosol, and the membranes of lysosomes, peroxisomes, mitochondria and other membrane intracellular organelles separate their contents from the cytosol. Biological membrane - semi-permeable barrier.

semi-permeable membrane. The biological membrane is defined as semi-permeable, i. a barrier that is impermeable to water, but permeable to substances dissolved in it (ions and molecules).

Semi-permeable tissue structures. Semi-permeable tissue structures also include the wall of blood capillaries and various barriers (for example, the filtration barrier of the renal corpuscles, the air-blood barrier of the respiratory section of the lung, the blood-brain barrier, and many others, although such barriers - in addition to biological membranes (plasmolemma) - also include non-membrane components. The permeability of such tissue structures is considered in the section "Transcellular Permeability" Chapter 4 .

The physicochemical parameters of the intercellular fluid and cytosol are significantly different (see Tables 2-1), and the parameters of each membrane intracellular organoid and cytosol are also different. The outer and inner surfaces of a biological membrane are polar and hydrophilic, but the non-polar core of the membrane is hydrophobic. Therefore, non-polar substances can penetrate the lipid bilayer. At the same time, it is the hydrophobic nature of the core of a biological membrane that determines the fundamental impossibility of direct penetration of polar substances through the membrane.

Non-polar substances(for example, water-insoluble cholesterol and its derivatives) freely penetrate biological membranes. In particular, it is for this reason that steroid hormone receptors are located inside the cell.

polar substances(for example, Na+, K+ C1-, Ca2+ ions; various small but polar metabolites, as well as sugars, nucleotides, protein and nucleic acid macromolecules) do not per se penetrate biological membranes. That is why the receptors of polar molecules (for example, peptide hormones) are built into the plasma membrane, and the transmission of the hormonal signal to other cell compartments is carried out by second messengers.

Selective permeability- the permeability of the biological membrane in relation to specific chemicals) - is important for maintaining cellular homeostasis. optimal content in the cell of ions, water, metabolites and macromolecules. The movement of specific substances across a biological membrane is called transmembrane transport (transmembrane transport).

Cells. Binding to a signaling molecule (hormone or mediator) occurs on one side of the membrane, and the cellular response is formed on the other side of the membrane. Thus, they play a unique and important role in cell-to-cell communication and signal transduction.

Many transmembrane receptors consist of two or more subunits that act in combination and can dissociate upon binding to a ligand or change their conformation and move to the next stage of the activation cycle. They are often classified based on their molecular structure. The polypeptide chains of the simplest of these receptors cross the lipid bilayer only once, while many cross the lipid bilayer seven times (for example, G-protein-coupled receptors).

Structure

Extracellular domain

The extracellular domain is the region of the receptor that is located outside the cell or organoid. If the receptor polypeptide chain crosses the cell several times, then the outer domain may consist of several loops. The main function of the receptor is to recognize the hormone (although some receptors are also capable of responding to changes in membrane potential), and in many cases the hormone binds to this domain.

transmembrane domain

Some receptors are also protein channels. The transmembrane domain mainly consists of transmembrane α-helices. In some receptors, such as the nicotinic acetylcholine receptor, the transmembrane domain forms a membrane pore or ion channel. After activation of the extracellular domain (hormone binding), the channel can pass ions. In other receptors, after the binding of the hormone, the transmembrane domain changes its conformation, which has an intracellular effect.

intracellular domain

The intracellular, or cytoplasmic, domain interacts with the interior of the cell or organoid, relaying the received signal. There are two fundamentally different ways of such interaction:

The intracellular domain binds to effector signaling proteins, which in turn transmit the signal along the signal chain to its destination.
If the receptor is associated with an enzyme or itself has enzymatic activity, the intracellular domain activates the enzyme (or carries out an enzymatic reaction).

Classification

Most transmembrane receptors belong to one of three classes, distinguished by the main mechanism of signal transduction. Classify ionotropic and metabotropic transmembrane receptors. Ionotropic receptors, or receptors coupled to ion channels, are involved, for example, in the rapid transmission of synaptic signals between neurons and other target cells that can perceive electrical signals.

Metabotropic receptors transmit chemical signals. They are divided into two broad classes: G protein-coupled receptors and enzyme-coupled receptors.

G-protein coupled receptors are also called 7TM receptors (seven-transmembrane domain receptors, receptors with seven transmembrane domains). They are transmembrane proteins with an outer segment for ligand binding, a membrane segment, and a G protein-coupled cytosolic segment. They distinguish six classes based on the similarity of the structure and functions of the receptors, classes A-F (or 1-6), which, in turn, are divided into many families. This class includes sensory receptors and adrenoreceptors.

Like GPCRs, enzyme-coupled receptors are transmembrane proteins in which the ligand-binding domain is located outside the membrane. Unlike GPCRs, their cytosolic domain is not coupled to a G-protein, but itself has enzymatic activity or binds the enzyme directly. Usually, instead of seven segments, as in GPCRs, such receptors have only one transmembrane segment. These receptors may include the same signaling pathways as GPCRs. This class includes, for example, the insulin receptor.

There are six main classes of enzyme-coupled receptors:

Receptor tyrosine kinases - can directly phosphorylate tyrosine residues, both their own and for a small set of intracellular signaling proteins.
Tyrosine kinase-coupled receptors are not active enzymes themselves, but directly bind cytoplasmic tyrosine kinases for signal transduction.
Receptor serine-threonine kinases - can directly phosphorylate serine or threonine residues, both their own and for the gene regulation proteins to which they bind.
Histidine kinase-associated receptors activate a two-step signaling pathway in which the kinase phosphorylates its own histidine and immediately transfers phosphate to a second intracellular signaling protein.
Receptor guanylate cyclases directly catalyze the production of cGMP molecules in the cytosol, which act as a small intracellular messenger in mechanisms very similar to cAMP.
Receptor-like tyrosine phosphatases - remove phosphate groups from tyrosines of intracellular signaling proteins. They are called receptor-like because their mechanism of action as receptors remains unclear.

Regulation

In the cell, there are several ways to regulate the activity of transmembrane receptors, the most important ways are phosphorylation and internalization of receptors.

Notes

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