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Membrane proteins

Around thirty per cent of all cellular proteins are located in or on a biological membrane. Numerous diseases are associated with defects in these proteins. It is estimated that around 50 per cent of all drugs developed by the pharmaceutical industry in the future, will target the different membranes of cells. However, it is quite difficult to biochemically investigate biological membranes. These are the many reasons why many research groups and biotechnology companies are looking closely at cellular membranes.

The development of biological membranes was a major basis for the development of life on earth. The cell membrane surrounds the cell and separates it from its environment, thereby protecting cells against life-threatening influences as well as providing an enclosed area for life-supporting chemical reactions to take place. However, as a true barrier, the cell membrane needs to be able to do a lot more: for example, it must be able to transport the right substances from the intracellular space to the outside and vice versa; it must be able to translate the signals from communication partners into the language of the cell. The interior of cells also contains membrane systems that separate compartments with different milieus from each other. Mitochondria, chloroplasts and the endoplasmic reticulum can only produce energy or new proteins because they form a chemically distinct space. And the genes in the cell nucleus are protected against harmful influences by a bilayer.

Flexible and stable

Schematic of the lipid bilayer of biological membranes © Olaf Lenz

Biological membranes consist of a bilayer of liposoluble substances, the lipids. Natural bilayers are mostly made up of phospolipids which extend their hydrophilic heads into the aqueous medium at either side of the membrane and organise themselves into a two-layered sheet. The two lipophilic tails point towards the centre of the sheet, thereby creating a hydrophobic layer. This layer also contains cholesterol, which is also a lipid. Biological membranes are very flexible and can only be destroyed mechanically with difficulty. Water and other water-soluble molecules (for example ions) cannot pass through the membranes since they are rejected by the hydrophobic phase. In contrast, proteins with fat-soluble amino acid residues that are turned towards the outside, are able to incorporate into the lipid layer. Such proteins are referred to as membrane proteins and they have a broad range of functions. Proteins that span the entire membrane or are only anchored on either of the two sides, are referred to as transmembrane proteins or associated membrane proteins.

A broad range of functions

Crystal structure of the nicotinic acetylcholine receptor (nAChR), a ligand-controlled ion channel. © S. Jähnichen

The cell membrane is a natural barrier for ions. The difference in negatively and positively charged particles on each side of the membrane (for example, inside and outside the cell) leads to the generation of an electric potential, which is the basis for the flow of current in neurons or muscle cells. In addition, it is also the driving force of substance flows. These substance flows are mediated by specialised protein machines, so-called channel proteins or transporters. Besides the aforementioned tasks, biological membranes also function as the recipients and transmitters of signals. Transmembrane proteins, which are referred to as receptors, can bind external signalling molecules and alter their own configuration, a change that can be detected on the other side of the membrane by specialised proteins or membrane lipids, which then transfer the signal to other molecules, thereby inducing certain reactions in the cell or organelle.

Other tasks of biological membranes are specific for the space they enclose. For example, the cell membrane links cells with other cells by way of adhesion proteins, thereby keeping the tissue together. Antigen receptors on the surface of immune cells recognise foreign substances and induce immune reactions. The cell membrane also mediates the uptake (endocytosis) and release (exocytosis) of substances that cannot simply pass through the membranes or channel proteins. The release of certain substances is the basis for the transfer of information by neurotransmitters at synapses or by hormones in the blood.

Other membrane systems in the cell are equally as essential as those mentioned above. For example, the highly complex membrane proteins of the respiratory chain are located at the inner membrane of mitochondria. These proteins are huge machines that can transfer electrons from energy-rich carbon compounds to oxygen, a process that leads to the production of energy. Photosynthetic protein complexes located in the membrane of chloroplasts in plant cells absorb the light of the sun and produce energy-rich carbon compounds. The list of the broad range of functions of biological membranes is fairly long.

Fatal defects

From left to right: erythrocyte (red blood cell), thrombocyte and leukocytes (white blood cells). Antiphospholipid syndrome is characterised by antibodies against certain proteins and lipids in the membrane of thrombocytes. The thrombocytes coagulate with other cells in the blood vessels and cause blood clots (thrombosis). © Wikipedia

As biological membranes have such crucial functions, defects in their composition can have severe consequences. One such example is the antiphospholipid syndrome (APS), an autoimmune disease characterised by the production of antibodies against the phospholipids in the membrane of blood cells and against proteins associated with these phospholipids. This leads to the coagulation of blood and thrombosis. APS mainly affects women and can lead to pregnancy-related complications (miscarriage), lung embolism, cardiac infarction, stroke and kidney infarctions.

Membrane defects can lead to defective communication that might also have severe consequences. An example of such defects is one that affects the so-called death receptors in the cell membrane. These transmembrane proteins normally transfer signals from the neighbourhood of a cell to make the cell undergo apoptosis (cell death). This is very useful in cases when the cell divides in an uncontrolled way and endangers the tissue, as is the case with cancer cells for example. If the death receptors or downstream signalling pathways are defective the command to commit suicide can no longer be transferred into the cell interior. The cancer cell can no longer be controlled by its environment, which can lead to the unobstructed growth of a tumour.

Numerous diseases are associated with defects in biological membranes, not just cell membranes. In mitochondria, defects in certain membrane proteins can lead to disorders of the energy metabolism and hence to combined diseases of the energy-dependent tissue of the skeletal muscles, the heart or the central nervous system.

Pharmaceutical targets

Due to their importance for the correct functioning of cells, biological membranes are excellent targets for pharmaceutical therapies. A classic example of a drug that exerts its effect at a membrane is aspirin, which inhibits the membrane-associated proteins cyclooxygenase COX-1 and COX-2. This inhibition prevents the synthesis of prostaglandins, signalling substances that induce inflammatory reactions and the sensation of pain. Another example is neuraminidase inhibitors such as Tamiflu or Oseltamivir, two drugs that are used to treat flu caused by influenza viruses. Influenza viruses reproduce inside a host cell and subsequently “bud” on the host cell membrane, where they remain attached to a surface molecule of the host cell until the viral neuraminidase enzyme, which is anchored in the membrane of the virus envelope, cleaves the binding. This process can be inhibited by drugs and the newly hatched viruses are unable to spread.

However, investigating the components of a membrane is not easy. Biochemists find it difficult to produce large quantities of membrane proteins in bacteria, and it is even more difficult to purify these proteins. In order to exert their proper function in the lipid bilayer, the molecules need to be hydrophobic and usually clump together when researchers try to solubilise them. Moreover, membrane proteins are often part of networks with other membrane proteins, proteins of the cell interior and membrane lipids. It is becoming more and more clear that it is impossible to look at membrane proteins without taking this functional context into account. Therefore, protein biochemists that are able to develop efficient laboratory methods will in future be highly sought after.


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© BIOPRO Baden-Württemberg GmbH

Literature:
Alberts, Johnson, Lewis, Raff, Roberts, Walter: Molekularbiologie der Zelle; 4. edition 2004; WILEY-VCH Verlag GmbH & Co. KgaA, Weinheim
W.J. Zeller, H. zur Hausen (Ed.): Onkologie; Ecomed, Landsberg 1995, Loseblattausgabe

Website address: https://www.gesundheitsindustrie-bw.de/en/article/dossier/membrane-proteins