Membrane proteins are found embedded in thephospholipid bilayers across all living organisms and have a range ofstructures and functions.
The biological importance of these proteins is not tobe underestimated with a huge variation in structure and function. In 2006 itwas estimated that between 15 and 39% of the human proteome was for membraneproteins (Ahram et al., 2006)which considering other organisms such as E. coli and C. elegans are estimatedto have 31 and 21% respectively gives an understanding of how essential these structuresare (Almén et al., 2009).
The Variation of MembraneProteinsThefunction of such proteins varies with each structure, but according to Almén (2009) the most common groups arethe transporters, receptors and enzymes, essential items that allow a cell tocarry out most biological processes. Because membrane proteins are often theinterface between the cell and its external environment they are oftensignificantly affected by mutations and genetic diseases and so are regularly targetedby modern medicines. Unfortunately these proteins have in past been difficultto identify due to the process in which they were determined.
Multipassproteins and beta barrel structures have a large variation in active residuelocations so the most common hydropathy methods notoriously could not locate thepresence of an active region. However newer methods utilising impermeantreagents that label surface residues have had more success and so our number ofknown proteins has dramatically increased.Membrane Protein Structure and FunctionThere is a large variation in membrane proteinstructure but they all are based on the principal that they can anchorthemselves to the bilayer, whether permanently or not is insignificant. Whilstthe most common integral proteins completely penetrate the lipid bilayer otherperipheral proteins do not even pass the surface, sometimes simply attaching toother proteins. A number of different structures have been used to achievethis, predominantly using an ?-helix but also via lipids, oligosaccharides and?-barrels as well (Alberts etal., 2002).In order for many transporter membraneproteins to function they must penetrate the hydrophobic region of the bilayer,these are known as integral proteins (Campbell et al., 2017).
This provides a biological challenge thatis often solved in the secondary structure of the protein. According toPapachristodoulou (2014)an ?-helical conformation of around 20 amino acid residues is often used tocross the aliphatic membrane as it anchors them without the usage of covalentbonding. The overall structure is varied with an amphipathic helix of centralnonpolar amino acid core (White,1998) and hydrophilic regions often being kept outside of the cell membrane,allowing for interaction with both the internal and external environments ofcells and organelles. ChannelProteinsWhilst an amphipathichelix is a good indication of a transport protein, a single helix is not enoughfor movement to occur.
Molecules such as bacteriorhodopsin have multiplehelices that cross the membrane several times. These form a centralized ring arounda hydrophobic channel in which specific molecules can travel. In this example theamino acid chain criss-crosses over the membrane 7 times but it is estimatedthat a protein only requires 4 amphipathic helices to support a basic channelbetween the internal and external environment of the cell. These channels arenot in fact clear open gaps in the membrane, but are selective and often gated.
This is achieved through the positioning of amino acids at the opening andcentre of the channel, utilising the amino acid r-groups. Some proteins havebasic amino acids that repel any positive ions attracted to the hydrophobicregion in the gap. Others utilise largeor branched side chains to restrict the channel that molecules can pass through.Occasionally this is taken a step further with some proteins having the abilityto rotate their amphipathic helices, causing the chains blocking the channel tomove and opening the ‘gate’ for molecules to pass through. Although ?-helices are the mostcommon secondary structure in these integral proteins other structures such as inthe porins of bacteria and mitochondria use ?-barrels instead. These proteinsare far more porous to small molecules than those with helices as they have alarger surface area. This provides a large water filled channel which isdifficult to regulate and so often ‘leaks’ molecules, hence why it is rarelyseen in eukaryotic membranes.
These barrels are formed of a varying number of antiparallelstrands, often between 8 and 20 chains that alternate between charged anduncharged residues to give an internally hydrophilic and externally hydrophobicregion. This once again anchors the protein in the membrane as the regions resistreach each other, but still allow for lateral movement to occur (Papachristodoulou et al., 2014).Active CarrierProteinsChannel proteins require passive diffusionthe cell can also utilise carrier proteins to move molecules against these concentrationgradients using an electrochemical gradient or the hydrolysis of ATP.
This isneeded for energy to create a conformational change in the protein structure,allowing molecules to pass across the membrane (Almén et al., 2009). Carrierproteins are highly selective, often only having a single molecule or group ofmolecules they can move at one time. This is because most of these proteinsrequire to be bound to the molecule for transport to occur, so similarly to withenzymes, require a specific shape to be present. As a result of the selectivityand use of available energy, this process is far faster than in channelproteins.
For example a group of transporter proteins found within red bloodcells are estimated to be 50,000 times faster at moving glucose across theplasma membrane than had it been done passively (Campbell et al., 2017). A good example of the effectiveness of such proteins is in the sodium-potassiumpump used in nerve resting and action potentials. This process uses a carrierprotein that both transports ions and acts as an enzyme, hence its name Na+/K+-ATPase.This protein has several active sites that ions bind to, but it is the ATPwhich provides the energy for conformational changes to occur. ATP provides energyfor three Na+ ions to move out of the cell through a hydrolysisreaction in addition to binding a phosphate ion to the protein.
Two K+ions can then bind to the protein from outside the cell and are only releasedafter the phosphate group detaches. This changes the tertiary structure of theprotein again and moves to potassium into the cell. This is an example of auniporter as the ATP is directly involved in the conformational change andmolecules only move in one direction at a time. Action potentials occurincredibly quickly, with most Na+ potentials completing their cyclewithin milliseconds, they are a good comparison against the facilitateddiffusion rates of channel proteins (Nave, 2009).CotransportProteinsCarrier proteins don’t always use ATPfor conformational changes as the energy can be sourced from other molecules orions such as in cotransport. These proteins are either considered symporters orantiporters depending on how they work, and are often used in conjunction withuniporters.
Almost all glucose is absorbed in humans from the small intestine andkidney against a concentration gradient by the SGLT1 symporter protein which carriesout cotransport using sodium ions (Poulsen et al., 2015). In this case both sodium andglucose are required to be present outside of the epithelium for transport tooccur via the symporter. This does however require there to be at least oneconcentration gradient for this to occur, so the same Na+/K+-ATPase from axons isused to remove sodium from the epithelial lining (Brooklyn College, 2000). This is considered asymporter protein as sodium and glucose are moving in the same direction, anexample of an antiport system is in the treatment of heart failure with calciumions. Cardiac glycosides are highly similarin shape to cholesterol and so are examples of steroids and steroid glycosides.
They inhibit the action of Na+/K+-ATPase by taking up sodium into the cell thatthe enzyme is trying to remove it from, in essence creating an equilibrium withnot net movement. At the same time they transport Ca2+ into thecell, in the opposite direction to the movement of sodium. This has the effectof increasing the concentration of Ca2+ in the cytosol, stimulatinga contraction of heart muscles and helping start the heart beating again. It isimportant to note that these sodium glycosides are created as toxins byfoxgloves and so have to be used in precise amounts or else can be lethal (Papachristodoulou et al., 2014).