- The ABCs of membrane transporters in health and disease (SLC series): Introduction - ScienceDirect
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Besides the specific protein complement of each organelle, the lipid make-up of the bilayers surrounding organelles varies. Lipids are synthesized in the ER, and flippases move lipid molecules between leaflets of the bilayer. For organelles in the secretory pathway and the plasma membrane, lipid transport into these compartments is mediated by vesicular membrane traffic through the pathway.
The cholesterol concentration in membranes increases from the ER through the Golgi to the plasma membrane. Cholesterol makes membranes thicker and more rigid, so the low levels of cholesterol in the ER membrane render it thin and facilitate the insertion of newly synthesized membrane and secretory proteins.
PC becomes relatively less abundant through this pathway, with more found in the ER than at the plasma membrane. PS and PE are found throughout the secretory pathway in the cytosolic leaflet of the membranes. This differential lipid composition through the secretory pathway is achieved by targeting specific lipids into transport vesicles.
Proteins included in these vesicles act as labels and direct the lipids to the right compartment. Forward-moving anterograde vesicles destined for the plasma membrane are rich in cholesterol. Lipids also move backwards through the secretory pathway, from the plasma membrane towards the ER.
This is known as retrograde traffic.
Retrograde vesicles from the Golgi are enriched in lipids such as PC, which are concentrated in the ER. The lipid composition of the mitochondria is very different from that of the secretory pathway compartments. Mitochondrial membranes are much richer in PE and cardiolipin than is the ER. Cardiolipin is synthesized in the mitochondria and is predominantly confined to this organelle. As membrane proteins have evolved along with their organelles and surrounding lipids, it follows that different lipid compositions are required in different organelles for the optimum activity of the proteins within their membranes.
The activity of this carrier protein is dependent on the presence of cardiolipin, which is relatively abundant in mitochondrial membranes. The targeting of newly synthesized membrane and secretory proteins to the ER has already been briefly discussed. However, there are many different destinations within the cell to which a protein can be sent, and sometimes proteins are located in more than one of these. The signals and protein machinery that are required to target proteins to the correct compartment are many and various, and much of the detail of the exact mechanisms involved has yet to be clarified.
Traffic through the secretory pathway is by vesicular transport in both anterograde and retrograde directions. Proteins and lipids can be included and excluded from vesicles by various means in order to selectively determine which molecules move forward or backward through the pathway. Vesicles are coated with proteins that determine their destination. Proteins that travel in vesicles referred to as cargo are selected either by interacting with receptors in the vesicles or by directly interacting with the coat proteins.
The selection of cargo occurs at the budding stage, when the coat proteins begin to distort the donor membrane e. Once the cargo has been selected and the coat proteins have been assembled, the vesicle buds off and travels to the acceptor membrane e. The vesicle then fuses with the acceptor membrane, depositing its cargo and constituent lipids Figure The main events in vesicular transport of cargo are shown. Cargo is selected and packed into vesicles which are formed by coat proteins 1 and 2.
The GTPase Rab is also incorporated on the outside of the vesicle and facilitates the steps illustrated. The vesicle then travels along proteins of the cytoskeleton towards its destination following dissociation of coat proteins 3. The vesicle is tethered to the donor membrane with the help of tethering proteins and the SNARE complexes 4 , allowing membrane fusion and release of the cargo 5.
The formation and fusing of vesicles are energetically demanding, as these processes require the stable bilayer to be broken in order to pinch off a new vesicle, and then fused with a different membrane. Both energy and specialized protein machinery are required to overcome this energy barrier. Once the vesicle has budded, travelled through the cytosol and reached its destination, it must fuse with its receptor membrane. Again this is an energetically unfavourable process, and protein machinery has to be utilized in order to allow the fusion of two bilayers.
SNARE proteins are central to the process of vesicle fusion. Not only does this confer specificity in the targeting of vesicles, but also the SNAREs facilitate membrane fusion on arrival of the vesicle. This stable interaction is thought to provide the free energy necessary to enable the two membranes to become very close and fuse.
As the two bilayers become closer, the lipids in the two outer leaflets can come into contact with one another, thereby increasing the hydrophobic nature of the site and enabling the membranes to join, and overcoming the energy barrier. The transmembrane domains of the SNAREs are also believed to be involved in membrane fusion, as when they are replaced by lipids experimentally, fusion does not occur.
Upon fusion, the cargo enters the target compartment, and the lipids and membrane proteins that formed the vesicle diffuse into the target membrane. Determining the mechanisms of membrane budding is important for understanding how viruses such as the human immunodeficiency virus HIV produce new viral particles. Unlike the budding in the secretory pathway described earlier, HIV particles bud away from the cytoplasm, into the extracellular space.
This viral budding occurs in the same orientation as the budding that occurs within endosomes. The proteins which enable this budding are referred to as endosomal sorting complexes required for transport ESCRTs. Understanding more about these membrane budding and scission events is crucial to elucidating how viruses proliferate and how we can inhibit processes by means of drug interventions. As described earlier, a hydrophobic stretch of 20—30 amino acids with a basic N-terminus and a polar region at the C-terminus emerging from the ribosome causes the protein to be targeted to the ER, where synthesis is completed.
This hydrophobic stretch can be cleaved in the case of soluble proteins, or it can remain attached. An uncleaved signal sequence is referred to as a signal anchor sequence, as it both signals ER targeting and then goes on to anchor a protein in the membrane, and becomes a transmembrane domain in the fully folded protein.
The SRP-dependent targeting step is common to ER proteins as well as proteins destined for the Golgi or the plasma membrane, or to be secreted from the cell.
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ER exit is thought to allow some selection of which proteins remain in the ER and which proteins leave and move in vesicles towards the Golgi. It is not understood exactly which properties of a protein determine whether it will leave the ER in COPII vesicles, but it is currently thought that the transmembrane domain length is an important factor.
Longer transmembrane domains appear to predispose proteins to exit the ER and travel towards the Golgi. This is consistent with the fact that membrane thickness increases through the secretory pathway due to increased cholesterol content, as described earlier. Upon arrival at the cis -Golgi, proteins can then be retrieved to the ER, remain in the Golgi, or travel onward to the plasma membrane. Retrieval to the ER is not fully understood, but some proteins contain retrieval motifs, such as the KDEL four-amino-acid motif which is recognized by a receptor and enables packaging of the protein into retrograde COPI vesicles.
Other proteins appear to cycle between the ER and the Golgi without known retrieval motifs. Proteins move in both anterograde and retrograde directions through the Golgi stack.
The ABCs of membrane transporters in health and disease (SLC series): Introduction - ScienceDirect
They can then leave the trans -Golgi and move to the plasma membrane in vesicles. Proteins at the plasma membrane can move into the cell in vesicles by endocytosis e. Endocytic vesicles are often clathrin coated. Clathrin, like the COPs, distorts the membrane into curved structures, allowing vesicle formation. Clathrin forms a cage-like shape that promotes vesicle formation and scission by virtue of the rigid shape of the protein complexes which form at the membrane.
Not all endocytosis is clathrin dependent, and there are other proteins, such as caveolin, which can facilitate the formation of endocytic vesicles. Newly synthesized proteins destined for the mitochondria or the nucleus are targeted in a different way, independently of the secretory pathway. Some mitochondrial proteins are encoded by the mitochondrial genome, while others are encoded by the nuclear genome.
Mitochondria have a double-layered membrane. Therefore targeting signals for mitochondrial proteins need to contain information not only to direct the protein to the organelle, but also to determine in which membrane it will be located in the case of membrane proteins , or whether it will be located inside the mitochondria the matrix or in the intermembrane space between the inner and outer membranes in the case of soluble proteins. Mitochondrial targeting motifs vary enormously, but generally are located at the N-terminus of the protein and are rich in positively charged and hydrophobic amino acids.
Proteins destined for the nucleus are targeted by nuclear localization sequences that direct proteins which have been synthesized in the cytoplasm through nuclear pore complexes. Again these sequences are not very highly conserved, but generally contain clusters of positively charged amino acids. We have already seen how ion channels and other transport proteins can allow substances to cross the lipid bilayer. Knowledge of how fat-soluble and water-soluble substances cross membranes is important for gaining an understanding of how messages cross membranes and thus how one cell can communicate with another.
Cells receive and send messages constantly e. Substances that send messages are known as messengers, and they vary enormously in their chemical composition, size and hydrophobicity. In order to understand how a cell receives a message, it is important to ascertain first whether the messenger is lipid or water soluble. Hormones are one example of messengers that are released by cells.
The human body contains both lipid-soluble and water-soluble hormones. Lipid-soluble hormones are generally transported through the blood, bound to carrier proteins. Steroid hormones such as the androgens and oestrogens are lipid soluble by virtue of their ringed molecular structures, which are derived from cholesterol. This allows these hormones to diffuse freely through the plasma membrane of cells and bind to their receptors, which are located inside cells. In the case of oestrogen, the receptor is located in the cytoplasm and upon ligand binding relocates to the nucleus, where it binds DNA and acts as a transcription factor, altering gene expression.
The receptor contains a nuclear localization sequence which is hidden until oestrogen binds, allowing it to be targeted to the nucleus. Other hormones, such as insulin and adrenaline, are water soluble and therefore cannot pass freely through the membranes of cells. Their receptors are located on the outside of the plasma membrane in order for them to be able to convey a message without entering cells.
Insulin binds to the membrane-spanning insulin receptor on the surface of target cells, and initiates a signal cascade that results in an increase in the number of glucose transporters at the cell membrane, and a subsequent increase in glucose uptake. Many cell-surface receptors share structural features, including seven membrane-spanning helices.
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These 7TM receptors bind their ligand the messenger molecule on the extracellular side of the membrane, and bind a GTP-binding protein G protein on the intracellular side. When the ligand binds the GPCR, the receptor undergoes conformational changes that are transferred through the membrane-spanning region to the bound G protein. This change in structure allows the G protein to exchange a bound GDP molecule for a GTP molecule, and thereby switch from an inactive state to an active state.
The effect of this adenylate cyclase activation is an increase in cAMP production from ATP, leading to downstream effects. The ligand bound to the GPCR is shown in red. These then have downstream effects on a range of proteins, thereby propagating the signal from the bound ligand. Yellow arrows indicate either activation up arrow or inhibition down arrow of the targets. After the initial ligand interaction with the GPCR and the G-protein dissociation, the message is then carried by second messengers activated by the signal cascade.
PKA phosphorylates target enzymes to modify their activities. In the case of adrenaline, PKA activates enzymes involved in the production of glucose from glycogen stores, and inhibits enzymes involved in the production of more glycogen. As explained earlier, membrane proteins are notoriously difficult to crystallize due to their hydrophobic nature, and GPCRs have a very small hydrophilic area. Some techniques, such as the production of an antibody—receptor complex to increase hydrophilicity, have been successful in aiding crystallization. Since then, several more GPCR structures have been solved, providing valuable information that can help computational biologists to work out the detailed mechanisms of GPCR signalling.
Molecular dynamics simulations have been performed on the interactions between GPCRs and their partner G proteins using the crystal structures available to inform the modelling process. These studies will play an important part in helping us to understand how the helices in the GPCRs move and twist in order to convey the extracellular signal to the intracellular G protein.
A ribbon representation of the first crystal structure of rhodopsin is shown in the plane of the membrane a and from the cytoplasmic side b. Adapted from Figure 2 from Palczewski, K. Science , — Nerve impulses are able to occur because biological membranes are impermeable to ions, so a membrane potential can be generated across them, with more of one charge on one side than on the other. These membrane potentials are generated and altered by ion channels. A nerve impulse, or action potential, is generated when a membrane is depolarized upon influx of positively charged ions into the cell.
This influx of positive charges enables the inside of the cell to become positively charged compared with the extracellular environment, as the membrane potential exceeds 0 mV. An after-potential hyperpolarization can then occur, whereby the membrane potential decreases below —70 mV before being restored by the action of ion channels and ATPases. We have seen how membranes, and the membrane proteins within them, function in healthy cells and organisms. We shall now consider what happens in disease, and how we can use our knowledge of membrane proteins to make new drugs to treat disease.
Cystic fibrosis is an autosomal recessive disease that results from mutations in the CFTR gene. Like nearly all membrane proteins, CFTR is translated on ribosomes at the ER and then moves through the secretory pathway to the plasma membrane, where it carries out its transport role. The single amino acid deletion of F causes the protein to misfold, and instead of moving out to the plasma membrane, it is held in the ER by the protein quality control machinery. Diseases such as this are not easily treated. Blocking the protein quality control machinery is not an option, because it would lead to the release of other misfolded proteins, with potentially disastrous consequences.
Although some current drug treatments can ameliorate the symptoms of the disease, it is hoped that gene therapy might become routine as it addresses the cause of the problem.
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Treatment of patients with an artificial, functional version of the gene enables them to produce a working CFTR protein that can be expressed at the plasma membrane. Although this is not a complete cure, it is a potentially effective way to greatly reduce the symptoms of cystic fibrosis in the lungs. As DNA is a large hydrophilic molecule, it cannot be simply administered like many other drugs. Delivery of gene therapy is a challenge, and this is one reason why it is difficult to treat patients in this way, but methods of delivering new genetic material into cells have been developed.
Patients may also be able to be given liposomes containing the functional gene, which fuse with cell membranes and deliver the therapeutic gene. Gene therapy is a growing and important area of research, and it is hoped that many diseases, including some cancers, will eventually be able to be treated using DNA. Viruses that attack the human body can use the body's own membrane proteins to recognize their target cells. HIV attacks cells of the immune system. A protein on the surface of HIV called gp binds to CD4 protein molecules on the surface of T-cells that are involved in immunoregulation, and allows fusion of the virus with the host cell.
Once the contents of the virus have entered the CD4-positive cell, the HIV genome is integrated with the host genome and uses the host machinery to make new copies of the virus. Over time, the numbers of CD4 T-cells are reduced by the virus, and the patient's immune system eventually becomes so compromised that they are unable to fight invading pathogens. Many therapeutic agents have been created to help to fight HIV, and the interaction between CD4 and gp is just one of the points at which drugs can be used to stop the progression of the virus.
Various toxins interfere with the transmission of messages across biological membranes. Tetanus neurotoxin TeNT and botulinum neurotoxin BoNT are both protein toxins that affect nerve impulse transmission between nerves and muscles. TeNT is produced by a soil bacterium and causes the skeletal muscle spasms that characterize tetanus infection. TeNT-producing bacteria generally enter the body through wounds, and TeNT binds glycolipids enriched at presynaptic membranes of motor neurons Figure TeNT then undergoes endocytosis and moves up the axon to the dendrites that connect the motor neuron to an inhibitory interneuron.
TeNT is released into the synapse between these two cells and is endocytosed into the inhibitory interneuron. Acidification of vesicles containing TeNT causes the protein toxin to break apart into two domains. One of these, the L domain, is translocated into the cytoplasm of the interneuron, where it uses its proteolytic activity to cleave vesicle-associated membrane protein VAMP.
Under normal circumstances, VAMP is part of the protein complex that allows synaptic vesicles to fuse with the presynaptic membrane and release inhibitory neurotransmitters. As this occurs in inhibitory interneurons, the resulting effect is prolonged skeletal muscle contraction, as no inhibition is conveyed to the motor neuron to allow relaxation. Tetanus toxin blue circles enters the presynaptic membranes of motor neurons by endocytosis, and moves up the axon to the dendrites that connect the motor neuron to an inhibitory interneuron.
Microtubules blue and green lines and actin filaments red lines allow retrograde transport of the toxin. TeNT acts on the inhibitory interneuron, where it prevents the release of glycine red dots , shown by a red cross. Small green dots represent neurotransmitter both inside and being released from vesicles. Adapted from Figure 2 from Rossetto, O.
Toxicon 66 , 59— Botulinum neurotoxin acts in a similar way to TeNT, but has the opposite effect. Like TeNT, it is released by bacteria. BoNT binds to and is internalized by the presynaptic membrane of motor neurons at the neuromuscular junction. Read more Read less.
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