Proteins are made up of amino acids which undergo various stages of folding to form their shape and structure. They are abundant in the body and have different functions, including structural, regulatory, contractile, and protective roles.
In this article, we will discuss the structure and function of proteins, and consider their clinical relevance.
Amino acids are the basic building blocks of proteins. Their structure consists of three main groups as seen in Figure 1, namely the amino group or N terminus, carboxyl group or C terminus and the R group which contains the functional component of the amino acid. The R group gives the amino acid specific features according to its polarity and charge, which then affect the chemical and biological properties of the protein.
There are a total of 21 amino acid types based on their different R groups. 12 of these can be synthesised in the body, while the other 9 must be consumed in the diet, hence are termed essential amino acids.
Protein structure can be divided into four main categories depending on level of complexity.
Peptide bonds between amino acids form the primary structure. Formation of hydrogen bonds between this initial structure leads to the formation of the secondary protein structure.
Folding of this polypeptide chain into a 3D shape forms the tertiary structure, and finally the combination of multiple polypeptide chain leads to formation of the quaternary structure.
These different stages will now be explored in more detail below:
Primary protein structure is defined as multiple amino acids bound together via strong covalent peptide bonds to form a polypeptide chain. These bonds form between the N terminal and C terminal of consecutive amino acids, and are highly resistant to heat or chemicals.
Any mutation in this amino acid sequence can affect protein folding in the subsequent stages of protein structure, leading to problems with the protein’s function.
Secondary protein structure is the repetitive folding of polypeptide chains by hydrogen bonds between the hydroxyl (OH) group and the hydrogen molecule of the adjacent amino acid, leading to the unique shape of the protein. The most common examples are the alpha-helix and beta-pleated sheets.
- The alpha-helix is a coil formed by hydrogen bonds between the carbonyl group and the amino group of different amino acids. The strong bonds and stability of this structure gives it a strong tensile strength, which allows it to form the shape seen in DNA.
- A beta-pleated sheet is formed by hydrogen bonds between the carboxyl group of one amino acid on one sheet and the hydrogen molecule of an amino acid on another sheet. The sheets can be in parallel or anti-parallel.
Tertiary protein structure is the folding of the polypeptide chain into a unique 3D structure. This tends to be globular in shape and contains a binding site for the protein action. Folding of the polypeptide chain occurs via interaction between the R groups of amino acids.
The tertiary structure can therefore be deranged once there is disruption to the bonds between R groups. This causes the structure to lose its shape, resulting in a loss of function. This is known as protein denaturation.
The type of bonds involved in formation of the tertiary protein structure include hydrogen bonds, electrostatic or ionic bonds, covalent bonds or hydrophobic bonds.
- Hydrostatic bond – forms between the hydroxyl (OH) group and an adjacent hydrogen molecule, providing a strong bond between polar R groups.
- Electrostatic bond – forms between positive and negative charge. They can be disrupted by presence of other charged molecules near them.
- Covalent disulphide bond – form between sulphide groups within the R group of amino acids. They usually occur between two cysteine amino acids, which contain sulphur within their R groups.
- Hydrophobic bond – form between non-polar groups and commonly involve the benzene group.
Quaternary protein structure is the combination of multiple polypeptide chains that link together to form a functioning unit. It is formed via bonds between the R groups of different amino acids within the polypeptide chains, which help to give the protein its shape.
When in its quaternary structure, the protein is fully functional and able to perform its specific role(s) within the body. Examples of quaternary protein structures include hormones like insulin, haemoglobin, enzymes and intracellular signalling structures.
Clinical Relevance – Sickle cell disease
Normal haemoglobin molecules have a globular shape due to the complex folding patterns of their polypeptide chains, allowing it to perform its function in oxygen transport.
However, in sickle cell disease, a genetic mutation leads to a change in an amino acid from glutamic acid to valine. This changes the shape of the haemoglobin subunit, and hence leads to changes in its folding. This underpins the pathophysiology of sickle cell disease.