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The cell. 3. Cell membrane.

ASYMMETRY, FUSION, REPAIRING

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Asymmetry.

The two membrane monolayers contain different molecular composition.

In the rough endoplasmic reticulum, proteins are synthesized and oriented in the membrane.

Although smooth endoplasmic reticulum synthesizes most of the lipids, the final position of lipids in the membrane may change depending on the membrane where they are located.

Endoplasmic reticulum and Golgi complex synthesize and place the carbohydrates in the inner monolayer, which will be the outer monolayer of the plasma membrane.

Different electro-chemical environments are created at both sides of membranes.

Fission and fusion.

Fusion and fission, mostly driven by proteins, allow to unite and separate membranes.

Repairing.

Cell membranes are easily damaged.

There are two repairing mechanisms: based in the physicochemical properties of lipids and based in the fusion of organelles with the damaged membrane.


Asymmetry

Cell membranes are made up of two lipid monolayers. In plasma and organelle membranes there is one monolayer facing the extracellular space or the interior of the organelle, respectively, whereas the other monolayer usually faces the cytosol. Lipids, carbohydrates and peripheral proteins are present in different types and proportions when both monolayers are compared. Moreover, transmembrane proteins are placed in the membrane with a precise orientation. This unequal distribution of molecules between both monolayers was known even before the fluid mosaic model of membrane was proposed in 1972. Create and maintain this asymmetry is essential for the cell.

In plasma membrane, the outer monolayer contains most of the lipids having choline, such as phosphatidylcholine and sphingomyelin, whereas the inner monolayer contains phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine. This is useful because it sets an unequal electrical charges distribution at both sides of the membrane, which helps to produce the membrane potential. Furthermore, it allows the association of specific proteins with the membrane due to the distinct electrochemical environment created by the electrochemical properties of lipid heads, which is different between both sides. The location of some lipids in a particular monolayer is important. For example, phosphatidylinositol is located in the inner monolayer of the plasma membrane and can be splitted in two molecules by some phospholipases, one molecule travels through the cytosol working as a second messenger. Furthermore, carbohydrates are located in the outer monolayer of the plasma membrane, contributing to the asymmetry. This unequal distribution also provides physical properties to membranes. For example, it is thought that it makes easier the formation of vesicles toward the cytosol, i.e. membrane foldings are favored toward the cytosol.

Disorganization of the membrane asymmetry usually brings pathological changes. For example, during apoptosis (programmed cell death), the outer monolayer of the plasma membrane exhibits lipids which are typical of the inner monolayer. These lipids are recognized by macrophages that finally remove the cell.

Where is the asymmetry created? Asymmetry of proteins is created in the rough endoplasmic reticulum, during protein synthesis. However, proteins associated to the cytosolic monolayer are synthesized in the cytosol by free ribosomes. The asymmetry of lipids in the plasma membrane is mainly due to Golgi complex, in other organelle membranes is set locally. In the endoplasmic reticulum is found a nearly symmetrical distribution of lipids between both monolayers. It is hard for lipids to move from one monolayer to the other (known as "flip-flop" movement) because of the barrier created by the hydrophobic environment of fatty acid chains. In membranes, there are transporters that make easy this movement: flippases, floppases and scramblases. These proteins change the position of lipids between both monolayers, thus modifying the membrane asymmetry. Flippases move lipids to the outer monolayer, floppases to the inner monolayer and scramblases mix lipids between both monolayers. Without these proteins the lipid distribution in the two membrane monolayers is maintained. Carbohydrates are directly synthesized in the outer monolayer by enzymes located in the lumen of the endoplasmic reticulum and Golgi complex.

Repairing

One the most useful properties of membranes is the ability to be separated and united again, i.e. fission and fusion of membranes. This feature allows organelles to growth, divide, to fuse between each other, and release little chunks from a source compartment such as vesicles that travel through the cytosol and become fused with a target compartment. It is also needed during animal cell cytokinesis, where the total cell membrane must be enlarged by new membrane addition, get breakage at some place, and become fused again to split the cytoplasm into the two daughter cells. Fission and fusion of membranes is mainly ruled by proteins, such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor), and also by membrane lipids.

A number of natural processes and experimental conditions may lead to membrane breakages. For example, cloning protocols in the laboratory need to introduce large glass micropipettes into the oocytes through plasma membrane, poration of membranes is needed to introduce DNA or vectors, handling of cells in cultures produces mechanical loads that break cell membranes. But some tissues are also under natural mechanical forces that compromise the membrane integrity, as in the muscular tissues. Cells have repairing mechanisms to avoid the lost of the internal content. This process of mixing internal and external environment must be stopped in seconds, otherwise cells die.

Membranes repairing
When membrane breakages are smaller than 0.2 µm, molecular properties of lipids are enough to close the gap (modified from McNeil and Steinhardt, 2003).

There are two mechanisms for repairing membranes depending on the type of damage. When the breakages are small (usually smaller than 0.2 µm), the physicochemical properties of lipids are able to repair the damage. At the edge of the membrane gap, lipids adopt an inestable disposition that push the edges against each other so that eventually close the hole. How quick is this sealing depends on the membrane tension, which in turn depends on the anchoring points between plasma membrane and both cytoskeleton and extracellular matrix. When a hole is made in the plasma membrane, calcium enters into the cytosol by concentration gradient, and the calcium concentration increase disorganizes the cytoskeleton around the damaged area, decreasing the contacts between cytoskeleton and plasma membrane. Then we have less membrane tension, and therefore a faster sealing of the gap. When damages are larger (more than 0.2 - 0.5 µm), the edges of the hole are too far apart and no auto sealing is possible. In this situation, a massive exocytosis takes place, and not just vesicles are participating but other larger organelles too. The process is as follow: the large hole allows the entering of a huge amount of calcium that produces the fusion of membrane compartments located close to the damaged area between each other; a large membrane compartment is formed which is eventually fused with the plasma membrane and closes the hole. Among the compartments involved are endosomes, lysosomes, vesicles and other non specialized compartments. Lysosomes are particularly important in this process.

Membrane repair

When membrane breakages are large, more than 0.2 - 0.5 µm, there is a massive entrance of calcium that triggers the fusion of organelles by a process similar to exocytosis. Organelles are moved to the damaged area and finally join to the cell membrane (modified from McNeil and Steinhardt, 2003).

Cells and tissues show mechanisms to adapt to repetitive mechanical stretching, and potential damages in their membranes: extracellular matrix changes its protein content, there is an increase in the number of adhesión molecules in plasma membranes, there is a development of the intermediate filaments of the cytoskeleton, and membranous organelles increase in number and size. Cellular responses to mechanical stress can be studied in cell cultures. It has been observed that stretching of about 10 to 15 % increase the membrane surface by fusion of internal organelles. This usually happen in the urinary bladder epithelium, which frequently undergoes large stretchings. When cells in cultures are stretched two times, a faster repairing process can be observed in the second one when compares with the first one. Furthermore, the amount of vesicles released by Golgi complex is larger than usual, so that cell may respond more efficiently when membranous compartments must fuse between each other. The cell attachment to the extracellular matrix is also strengthened. The fibrous protein of the cytoskeleton and in the extracellular matrix increase in number to withstand repetitive mechanical tensions.


Bibliography

Daleke DL. 2007. Phospholipid flippases. The journal of biological chemistry 282:821-825.

McNeil PL, Steinhardt RA. 2003. Plasma membrane disruption: repair, prevention, adaptation. Annual review in cell and development biology. 19:697-731.

Nicolson GL. 2014. The fluid-mosaic model of membrane structure: still relevan to understanding the structure, function and dynamics on biological membranes after more than 40 years. Biochimica and biophysica acta. 1838: 1451-1466.



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Updated: 2017-09-11. 13:02