Cell Membrane


Membranes[Edit]

Plasma membranes are subcellular structures, approximately 10nm thick, that form a protective boundary around the cell as well as the cell’s organelles. They serve to both impede foreign material from entering the cell, and prevent the cellular contents from leaking out. With the structural makeup of the lipid bilayer conferring membranes unique physical and chemical properties, these structures also contribute to diverse and critical cellular functions.

Membranes are composed of lipids and proteins, in equal proportions by mass. The current views on membrane structure are derived from the Fluid-Mosaic Membrane Model (F-MMM)[1], which depicts them as two-dimensional fluids made up of lipid-bilayers interspersed with proteins. The fluidic nature of membranes is due to the constant rotational or lateral motion of both lipids and proteins. While lipids provide the basic structure of membranes, the proteins carry out a vast array of specialized functions, from ion and small molecule transport to the regulation of signalling pathways.

Types of membrane lipids[Edit]

Membrane lipids are amphipathic, which means that they have a polar or hydrophilic end and a non-polar or hydrophobic end. In aqueous mediums, membrane lipids spontaneously organize into bilayers with the polar ends oriented towards, and the non-polar ends oriented away from, the solution. The bilayer closes in on itself to avoid free edges with water. These basic structural properties of plasma membranes enable them to carry out their fundamental functions. For example, the propensity of membrane lipids to form a thermodynamically stable, closed lipid bilayer structures renders them stability and encourages the formation of closed subcellular compartments. It also enables the spontaneous repair of small tears in the membrane, which prevents material leaking out of the cell or organelles. Furthermore, the hydrophobic interior of membranes serves as a barrier to water soluble molecules but allows certain lipid soluble molecules to passively diffuse through. Membranes are therefore selectively permeable structures; a property that helps to prevent leakage and protect the cell from the passive entry of many toxins.

Figure 1. General structure of phosphoinositides: The composition and length of the hydrocarbon tail is somewhat diverse and is reported to range from 16 carbons to 22 carbons. For simplicity, the glycerol backbone in this illustration is represented by a brown box, and the oxygen atoms of the inositol head group have been omitted. Chemical modification to the inositol ring occurs in the conversion of phosphatidylinositol to other phosphoinositides to other phosphoinositides

Membrane lipids are highly diverse, with a typical membrane containing more than 100 species of lipid. These lipids vary in their structure and extent of saturation of the fatty acyl chains.

There are three major classes of membrane lipids – the phosphoglycerides, sphingolipids and sterols.

The phosphoglycerides and sphingolipids can be combined as one class, the phospholipids. These are the classical membrane lipid, formed of a polar head group and two hydrophobic fatty acid tails. The fatty acid tails typically contain between 14-24 carbon atoms. One of the two tails is unsaturated and therefore contains one or more cis-double bonds, which creates a small kink in the tail. The other tail is saturated, without any cis-double bonds and remains straight. Variations in the length and saturation of the fatty acid tail affect how tightly phospholipids are able to pack against each other, leading to altered membrane fluidity. Linking the polar head group to the fatty acid tail is a backbone made up of either glycerol or sphingosine. The different backbone molecule differentiates between the classes of phospholipid.

Phosphoglycerides have a polar head group esterified to one of three glycerol hydroxyl groups, and two hydrophobic fatty acid tails esterified to the remaining two hydroxyl groups of the glycerol backbone. The polar head group is composed of a phosphate group linked to choline, ethanolamine, serine or inositol. These form phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidyl serine (PS) and phosphatidylinositol (PI) respectively.

Sphingolipids, on the other hand, have a backbone formed from sphingosine, an amino alcohol with a long hydrocarbon chain; a less abundant class of membrane lipids. Ceramide is a simple sphingolipid which has a hydrophobic fatty acid tail linked to the amino group of the sphingosine. The esterification of additional groups to the terminal hydroxyl group of the sphingosine backbone gives rise to other types of sphingolipids. For instance, sphingomyelin has a polar phosphoryl choline head group and glycolipids have a carbohydrate group. The carbohydrate group of glycolipids can be a simple sugar or an oligosaccharide forming cerebrosides and gangliosides respectively.

Sterols are smaller than phospholipids. They have a single polar hydroxyl head group attached to a rigid steroid ring structure and a short non-polar hydrocarbon tail. Cholesterol is the major sterol component of animal cell membranes. Different sterols are found in other eukaryotic cell membranes. Yeast and fungi use ergosterol, while plants use sitosterol and stigmasterol.  However, prokaryotic cell membranes essentially contain no sterols. Sterols insert into the lipid bilayer with their hydroxyl head groups oriented with the phospholipid polar groups. This aligns the rigid ring structure of the sterol with the phospholipid hydrocarbon tail, which decreases phospholipid mobility. This stiffening effect also reduces the water-soluble permeability of the bilayer but does not affect membrane fluidity.

Membrane Proteins[Edit]

While membrane lipids form the basic structure of the lipid bilayer, the active functions of the membrane are dependent on the proteins. Cell adhesion, energy transduction, signaling, cell recognition and transport are just some of the important biological processes carried out by membrane proteins.

Proteins can associate with the membrane in one of three ways. Intrinsic or integral membrane proteins embed in the hydrophobic region of the lipid bilayer. Experimentally, these proteins can only be isolated by physically disrupting the membrane with detergent or other non-polar solvent. Monotopic proteins insert in one leaflet but do not span the membrane.  Transmembrane proteins are the classic examples of intrinsic membrane proteins. These span the membrane, typically in an α-helix conformation and can span the membrane multiple times. Some intergral membrane proteins use β-barrels to cross the membrane. These structures are typically large and form water filled channels. Extrinsic or peripheral membrane proteins associate loosely with the hydrophilic surfaces of the lipid bilayer or intrinsic membrane proteins. They form weak hydrophobic, electrostatic or non-covalent bonds, but do not embed with the hydrophobic core of the membrane. These proteins can be dissociated from the membrane without disrupting it through application of polar reagents or high pH solutions. Extrinsic membrane proteins may interact with the inner or outer leaflet. 

Movement of Bilayer Components[Edit]

One of the tenets of the Fluid-Mosaic membrane model is that the components of the bilayers are free to move. Before describing the differences between lipid and protein movement in the bilayer, it is important to consider the types of movement possible. Using a phospholipid as an example, the first type of movement is rotational. Here the phospholipid rotates on its axis to interact with its immediate neighbours. The second type of movement is lateral, where the phospholipid moves around in one leaflet. Finally, it is possible for phospholipids to move between both leaflets of the bilayer in transverse movement, in a “flip-flopâ€? manner. 

Lateral movement is what provides the membrane with a fluid structure. By labelling single particles and following their movement via high speed video, researchers were able to discover that phospholipids did not move via Brownian motion but rather by “hop diffusion�. Phospholipids stay in one region for a short while before hopping to another location. This compartmentalization of lateral movement appears to be linked to contacts between the actin cytoskeleton and the membrane which form the regions that the phospholipids hop between.

As described above, membrane asymmetry is critical for membrane functions. Transverse movement is what allows the asymmetry to be maintained. Uncatalysed movement of phospholipids between the bilayers is possible, but this is slow and cannot be relied upon to maintain the asymmetry equilibrium. Instead, lipid translocator proteins catalyse phospholipid movement between the bilayers. Flippases move phospholipids from the outer leaflet to the inner leaflet. In order to maintain the charge gradient across the membrane, flippases predominantly transport phosphatidylserine and to a lesser extent phosphatidylethanolamine. Floppases move phospholipids in the opposite direction, particularly the choline derived phospholipids phospatidylcholine and sphingomyelin. Floppases also mediate cholesterol transport from the intracellular monolayer to the extracellular monolayer. These catalyzed movements are typically dependent on ATP hydrolysis. A third class of protein are the scramblases, which exchange phospholipids between the two leaflets in a calcium activated, ATP-independent process. 

In the case of membrane proteins, they are able to undergo rotational and lateral movement. However, there is no transverse movement of proteins between the leaflets. Intrinsic membrane proteins are tightly embedded in the hydrophobic core, whereas extrinsic membrane proteins associate with their required leaflet. The energy requirements to move either type of membrane protein across the bilayer would be excessive. 

Membrane lipid asymmetry[Edit]

The human red blood cell is functionally specialized for transporting oxygen. In order to maximize oxygen capacity, it has no nucleus or organelles, consisting primarily of plasma membrane and hemoglobin. This made it an ideal candidate for membrane studies. Interestingly, when scientists looked at the lipid bilayer of the red blood cell, they found that the phospholipid composition of the individual monolayers was quite different. The monolayers exhibited lateral heterogeneity, where specific lipids and proteins cluster together in a patchwork fashion. This diversity was enhanced by the observation of transverse asymmetry of lipids and proteins in the two leaflets of the bilayer.

The outer monolayer contained phospholipids with choline in their polar head group such as phosphatidylcholine and sphingomyelin. Conversely, inner monolayer phospholipids were those with a terminal primary amino group, namely phospatidylserine, and phosphatidylethanolamine. The phosphatidyl inositols are also located on the cytosolic side of the bilayer. Cholesterol is distributed evenly throughout the two monolayers. 

Although most phospholipids are neutral at physiologic pH, phosphatidylserine and phosphatidylinositol have a net negative charge at physiologic pH. Being present predominately in the inner leaflet, these two lipids generate a significant difference in charge between the two leaflets of the lipid bilayer. This generates a functionally relevant asymmetry in the membrane. In particular, membrane lipid asymmetry is important for signal transduction. Phosphatidyl serine is a binding partner for signaling proteins such as protein kinase C. However, the appearance of phosphatidyl serine on the outer leaflet of the cell membrane is an indication of a loss of membrane integrity. Extracellular expression of phosphatidyl serine targets the cell for engulfment by macrophages and is widely used as a diagnostic marker for apoptosis. Maintaining membrane lipid asymmetry is therefore highly important for cell homeostasis. 


Figure 2. Phosphoinositides involved in cell signaling.: This figure gives an example of how different phosphoinositides are produced from phosphatidylinositol by the action of two kinases (e.g., PI kinase and PIP kinase) and it shows how signaling molecules (e.g. PIP2, DAG, IP3) are generated. It should be noted that a number variations exist for which hydroxyl groups are phosphorylated, and not surprisingly, a number of kinases are involved in these phosphorylation events. DAG= diacylglycerol; IP3=inositol triphosphate.
Three main types of phosphoinositides have important roles in intracellular signaling, lipid signaling, and membrane trafficking; these phosphoinositides differ solely in the number of phosphate groups that are attached by phosphoinositol kinases to the inositol ring 

• Phosphatidylinositol-4-phosphate (PIP) – increased levels of PIP in the plasma membrane greatly reduces the F-actin binding and depolymerizing activity of ADF (actin depolymerizing factor).

• Phosphatidylinositol-4,5-bis-phosphate (PIP2) – increased levels of PIP2 in the plasma membrane inhibits actin filament capping by capping protein and greatly reduces the F-actin binding and depolymerizing activity of ADF.

• Phosphatidylinositol-3,4,5-trisphosphate (PIP3) – Phosphatidylinositol-3-kinase (PI3K) and PTEN (Phosphatase and tensin homolog) signal transduction pathways regulate the level of PIP3 in response to extracellular guidance cues during filopodia motility. The accumulation of PIP3 in filopodia is suggested to cause actin polymerization and increased cellular movement.

The membrane asymmetry in lipid and protein composition led to the proposal of the bilayer couple hypothesis. This states that the two monolayers of the membrane bilayer may respond differently to various forces while remaining coupled to each other. This hypothesis is the basis for the possible shape changes observed in membranes.

References

  1. Singer SJ., Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science 1972; 175(4023). [PMID: 4333397]
Updated on: Fri, 31 Oct 2014 09:07:31 GMT
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