Protein folding is a process by which, in its native 3D structure, a polypeptide chain folds to become a biologically active protein. The structure of proteins is crucial to their function. By different molecular interactions, folded proteins are held together.
Each protein is synthesised during translation as a linear chain of amino acids or a random coil which does not have a stable 3D structure. To form a well-defined, folded protein, the amino acids in the chain eventually interact with each other. A protein’s amino acid sequence determines its 3D structure. It is key to their function to fold proteins into their correct native structure. Inactive or toxic proteins that malfunction and cause a number of diseases are generated by failure to fold properly.
Four stages of protein folding
The folding of a protein is a complex four-stage process that gives rise to different structures of 3D proteins that are essential for various functions in the human body. The structure of a protein, from a primary to quaternary structure, is hierarchically arranged. The various conformations in the protein structure account for the broad variation in amino acid sequences.
- The primary structure refers to the linear sequence of residues of amino acids in the polypeptide chain.
- The secondary structure is created by the formation of hydrogen bonds in the polypeptide backbone between atoms, folding the chains into either alpha helices or beta sheets.
- The tertiary structure is formed by the folding of sheets or helices of the secondary structure into one another. The geometric shape of the protein is the tertiary protein structure. As a backbone, it generally has a polypeptide chain, with one or more secondary structures. The interactions and bonding of the amino acid side chains in the protein determines the tertiary structure.
- The quaternary structure is the result of folded amino acid chains interacting further with each other in tertiary structures to create a functional protein such as haemoglobin or DNA polymerase.
Factors affecting protein folding
Protein folding is a very sensitive process influenced by several external factors, such as electrical and magnetic fields, temperature , pH, chemicals, limitation of space, and molecular crowding. The capacity of proteins to fold into their correct functional forms is affected by these factors.
Extreme temperatures influence protein stability and cause it to unfold or denature. Similarly, proteins can be denatured by extreme pH, mechanical forces and chemical denaturants. Proteins lose their tertiary and secondary structures during denaturation, becoming a random coil. Although denaturation is not always reversible, under certain conditions, some proteins can re-fold.
Some cells contain proteins for heat shock or chaperones that protect the cell’s proteins against heat denaturation. Chaperones help proteins to fold and remain folded under extreme temperatures. They also help misfolded proteins to correctly unfold and re-fold.
Diseases related to incorrect protein folding
Misfolded proteins easily denature and lose their composition and function. A lot of human diseases can result from incorrect protein folding.
An example of a neurodegenerative condition caused by protein misfolding is Alzheimer’s disease. Dense plaques in the brain caused by misfolding of the secondary β-sheets of fibrillary β-amyloid proteins present in brain matter are characterised by this disease. Other examples of neurodegenerative diseases associated with protein misfolding are Huntington’s disease and Parkinson’s disease.
Cystic fibrosis (CF) is a fatal disease caused by the misfolding of the protein regulator of transmembrane conductance of cystic fibrosis (CFTR). Phenylalanine at position 508 of the CFTR is deleted in most CF cases, causing the regulator protein to be misfolded. It has also been shown that several allergies are caused by incorrect protein folding.