Membrane due to the process in which they were

Membrane proteins are found embedded in the
phospholipid bilayers across all living organisms and have a range of
structures and functions. The biological importance of these proteins is not to
be underestimated with a huge variation in structure and function. In 2006 it
was estimated that between 15 and 39% of the human proteome was for membrane
proteins (Ahram et al., 2006)
which considering other organisms such as E. coli and C. elegans are estimated
to have 31 and 21% respectively gives an understanding of how essential these structures
are (Almén et al., 2009).

The Variation of Membrane
Proteins

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The
function of such proteins varies with each structure, but according to Almén (2009) the most common groups are
the transporters, receptors and enzymes, essential items that allow a cell to
carry out most biological processes. Because membrane proteins are often the
interface between the cell and its external environment they are often
significantly affected by mutations and genetic diseases and so are regularly targeted
by modern medicines. Unfortunately these proteins have in past been difficult
to identify due to the process in which they were determined. Multipass
proteins and beta barrel structures have a large variation in active residue
locations so the most common hydropathy methods notoriously could not locate the
presence of an active region. However newer methods utilising impermeant
reagents that label surface residues have had more success and so our number of
known proteins has dramatically increased.

Membrane Protein Structure and Function

There is a large variation in membrane protein
structure but they all are based on the principal that they can anchor
themselves to the bilayer, whether permanently or not is insignificant. Whilst
the most common integral proteins completely penetrate the lipid bilayer other
peripheral proteins do not even pass the surface, sometimes simply attaching to
other proteins. A number of different structures have been used to achieve
this, predominantly using an ?-helix but also via lipids, oligosaccharides and
?-barrels as well (Alberts et
al., 2002).

In order for many transporter membrane
proteins 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 that
is often solved in the secondary structure of the protein. According to
Papachristodoulou (2014)
an ?-helical conformation of around 20 amino acid residues is often used to
cross the aliphatic membrane as it anchors them without the usage of covalent
bonding. The overall structure is varied with an amphipathic helix of central
nonpolar 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 of
cells and organelles.

Channel
Proteins

Whilst an amphipathic
helix is a good indication of a transport protein, a single helix is not enough
for movement to occur. Molecules such as bacteriorhodopsin have multiple
helices that cross the membrane several times. These form a centralized ring around
a hydrophobic channel in which specific molecules can travel. In this example the
amino acid chain criss-crosses over the membrane 7 times but it is estimated
that a protein only requires 4 amphipathic helices to support a basic channel
between the internal and external environment of the cell. These channels are
not 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 and
centre of the channel, utilising the amino acid r-groups. Some proteins have
basic amino acids that repel any positive ions attracted to the hydrophobic
region in the gap.  Others utilise large
or branched side chains to restrict the channel that molecules can pass through.
Occasionally this is taken a step further with some proteins having the ability
to rotate their amphipathic helices, causing the chains blocking the channel to
move and opening the ‘gate’ for molecules to pass through.

Although ?-helices are the most
common secondary structure in these integral proteins other structures such as in
the porins of bacteria and mitochondria use ?-barrels instead. These proteins
are far more porous to small molecules than those with helices as they have a
larger surface area. This provides a large water filled channel which is
difficult to regulate and so often ‘leaks’ molecules, hence why it is rarely
seen in eukaryotic membranes. These barrels are formed of a varying number of antiparallel
strands, often between 8 and 20 chains that alternate between charged and
uncharged residues to give an internally hydrophilic and externally hydrophobic
region. This once again anchors the protein in the membrane as the regions resist
reach each other, but still allow for lateral movement to occur (Papachristodoulou et al., 2014).

Active Carrier
Proteins

Channel proteins require passive diffusion
the cell can also utilise carrier proteins to move molecules against these concentration
gradients using an electrochemical gradient or the hydrolysis of ATP. This is
needed for energy to create a conformational change in the protein structure,
allowing molecules to pass across the membrane (Almén et al., 2009). Carrier
proteins are highly selective, often only having a single molecule or group of
molecules they can move at one time. This is because most of these proteins
require to be bound to the molecule for transport to occur, so similarly to with
enzymes, require a specific shape to be present. As a result of the selectivity
and use of available energy, this process is far faster than in channel
proteins. For example a group of transporter proteins found within red blood
cells are estimated to be 50,000 times faster at moving glucose across the
plasma membrane than had it been done passively (Campbell et al., 2017).

A good example of the effectiveness of such proteins is in the sodium-potassium
pump used in nerve resting and action potentials. This process uses a carrier
protein 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 ATP
which provides the energy for conformational changes to occur. ATP provides energy
for three Na+ ions to move out of the cell through a hydrolysis
reaction 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 released
after the phosphate group detaches. This changes the tertiary structure of the
protein again and moves to potassium into the cell. This is an example of a
uniporter as the ATP is directly involved in the conformational change and
molecules only move in one direction at a time. Action potentials occur
incredibly quickly, with most Na+ potentials completing their cycle
within milliseconds, they are a good comparison against the facilitated
diffusion rates of channel proteins (Nave, 2009).

Cotransport
Proteins

Carrier proteins don’t always use ATP
for conformational changes as the energy can be sourced from other molecules or
ions such as in cotransport. These proteins are either considered symporters or
antiporters depending on how they work, and are often used in conjunction with
uniporters. Almost all glucose is absorbed in humans from the small intestine and
kidney against a concentration gradient by the SGLT1 symporter protein which carries
out cotransport using sodium ions (Poulsen et al., 2015). In this case both sodium and
glucose are required to be present outside of the epithelium for transport to
occur via the symporter. This does however require there to be at least one
concentration gradient for this to occur, so the same Na+/K+-ATPase from axons is
used to remove sodium from the epithelial lining (Brooklyn College, 2000). This is considered a
symporter protein as sodium and glucose are moving in the same direction, an
example of an antiport system is in the treatment of heart failure with calcium
ions.

Cardiac glycosides are highly similar
in 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 that
the enzyme is trying to remove it from, in essence creating an equilibrium with
not net movement. At the same time they transport Ca2+ into the
cell, in the opposite direction to the movement of sodium. This has the effect
of increasing the concentration of Ca2+ in the cytosol, stimulating
a contraction of heart muscles and helping start the heart beating again. It is
important to note that these sodium glycosides are created as toxins by
foxgloves and so have to be used in precise amounts or else can be lethal (Papachristodoulou et al., 2014).