Introduction: subunit. Altogether, these two subsections make up

Introduction:

The term structure refers to the construction of something in
a 3-dimensional space made from the interactions of its components. In biology,
these objects may refer to proteins which are made up of amino acids monomers and
the interactions between these amino acids include hydrogen bonds and
disulphide bridges.

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Function refers to the purpose or role of something in its
environment. Within biology, this may refer to a process as a part of a larger
system or body arrangement.

The term protein, as briefly mentioned previously, refers
to a structure that is made up of amino acid monomers with specific
intramolecular interactions that allow it to form a 3D shape. Which as a result
causes it to have a distinctive function in a larger system.

The protein that will be explored and discussed in this
essay will be the Cholera Toxin.

Brief
background of the Cholera Toxin:

The cholera toxin was first identified in 1959 by Prof.
Sambhu Nath De at Kolkata (De, 1951)1. It
is a protein complex that is responsible for the cholera infection. It is
released by the bacteria, Vibrio cholerae.

Structure
of the Cholera Toxin:

The structure of the cholera toxin is an oligomeric one.
The term oligomer, dissimilar to a polymer, refers to the structure of a
protein being made up of a couple individual monomers compared to the vast
number monomers which make up a polymer. Oligomers are usually made up of 2-6
monomers (Wilkinson, 1997)2.
The cholera toxin is made up of 6 different monomers (protein subunits), 5 of
the 6 units belonging to the receptor binding component (5 B subunits) of the
protein and the final unit belonging to the part (1 A subunit) which is
responsible for metabolic reaction. Figure 1 shows the 5 B subunits of the
cholera toxin, and their pentagonal arrangement.

The enzymatic subunit is not shown in Figure 1; however, it
is shown in Figure 2. But we can see the side view of the pentagonal structure
of the 5 B subunits. Also, on top of that, the 1 A subunit. Altogether, these
two subsections make up the cholera toxin’s structure. The piece of protein
that joins these two subunits is a simple alpha helix which has a peptide link
at either end to keep the molecule as one unit. Collectively, it becomes an AB­­5
complex. The A subunit is divided into two smaller subsegments, A1 &
A2 (also known as CTA1 & CTA2 respectively) which is held together by a
disulphide bond (shown by a red circle in figure 3). This will be important
when discussing how structure of the toxin relates to the function.

 

Function
of the Cholera Toxin:

The overall function of the cholera toxin is to trigger the
CFTR (Cystic fibrosis transmembrane conductance regulator) to release more
chloride ions into the apical side of the membrane.

When the Vibrio Cholerae releases the Cholera toxin, it
interacts with the GM1 Ganglioside (by receptor-binding site interactions).
This causes the release of the A1 subunit into the Epithelial cell – this is
done via the breaking of the disulphide bond. This G-protein can now bind to the
Adenylate Cyclase which causes the production of the cAMP (cyclic AMP) which
then activates a PKA (protein kinase A). This then phosphorylates the CFTR
protein causing a greater concentration of chloride ions to be released. As a
result, Na+ follows the Cl- due to electrostatic
attraction, which then further causes water to follow due to the overall electrochemical
gradient. This causes an excess of water in apical membrane (of the intestine
cells) which leads to the organism who has been infected by the toxin to have
watery excrements.

Importance of structure on the function of
the Cholera toxin

The structure of the cholera toxin is crucially important
to its function. Having mentioned before that is has 5 subunits, it’s essential
for the actions that take place in the epithelial cells that the processing and
folding of the protein is done to perfection. Shown in figure 5 is the 5
receptor binding sites of the cholera toxin. Although they look very similar
initially, we can see that the coloured areas (indicating the different
electron density maps of each binding site) are different at key points of each
site. This indicates that distinctive areas of the receptor binding sites will
interact in a contrasting way to other areas (via electron overlaps). This
proves the influence of the structure of the function of the toxin. Receptor-toxin
binding sites must be totally complimentary for the whole molecule to
successfully activate the function of the toxin. Hence the relevance of the 3-dimensional
structure.

Furthermore,
as well as the initial interaction between the toxin’s B subunits and the
GM1-Ganglioside cell surface sphingolipid, the A subunit of the cholera toxin
is released into the epithelial cell. For this to occur, it must be small yet
accurately structured to allow it to pass the membrane. If the structure is too
big to fit through the membrane, then the action of the toxin is stopped.

Not
only this but as mentioned before there are two subsegments of the A subunit,
which are joined by a disulphide bond. If there was twice as many disulphide
bonds then the release of the A1 subsection may not be possible which will mean
the process shown in figure 4 will be halted, as nothing will be able to
activate the G-protein. On the other hand, if in place of the disulphide bond
there was a hydrogen bond (which is much weaker), the resulting effect will be
that the bond might break on its way to the epithelial cell, which will then
mean although the five B subunits will attach onto the GM1 ganglioside, there
will be no A1 subunit present to release into the cell, hence having no onset
effect on the CFTR protein.

 

Conclusion: To conclude, the structure of the cholera toxin is
essential in its function. With many components that make up the toxin’s
structure it is vital that everything works in unison – most significantly with
5 receptor binding sites of the toxin.

References

1.   
De, S. N. et al. (1951). An experimental study of the action of cholera
toxin. The Journal of Pathology. 63 (1), 707-717.

2.   
Wilkinson, A.D. (1997). Oligomer Molecule.
Available: http://goldbook.iupac.org/html/O/O04286.html. Last accessed 26th Dec
2017

 

3.   
Merritt, E.A. (1995). Cholera toxin B pentamer,
Vibrio cholerae. Available: http://www.rcsb.org/pdb/explore/explore.do?structureId=1chq.
Last accessed 25th Dec 2017.

4.    De
Haan L. (2004). Cholera toxin: a paradigm for multi-functional engagement of
cellular mechanisms. PubMed. 21 (2), 77–92.

5.   
Mudrak, B. (2010). Heat-Labile Enterotoxin:
Beyond GM1 Binding. Available: http://www.mdpi.com/2072-6651/2/6/1445/htm. Last
accessed 28th Dec 2017.

 

6.   
Mclaneb1. (2016). Cholera Toxin Mechanism.
Available:
https://upload.wikimedia.org/wikipedia/commons/c/ce/CholeraToxin.png. Last
accessed 25th Dec 2017.

 

7.   
Wim G. J. Hol. (2012). The cholera toxin
family: Action and Inhibition. Available:
http://www.bmsc.washington.edu/WimHol/figures/figs2/WimFigs2.html. Last
accessed 27th Dec 2017.