As complex organisms, humans require thousands of proteins in order to function. Each protein has a specific shape and role within the body to ensure survival and when these proteins fail to work we often see large scale impacts across many cells, tissues and organs. During translation, a strand of mRNA gets interpreted from a sequence of nucleotides into a sequence of amino acids to form a polypeptide chain. (Biology Online Dictionary, 2017) Some proteins require modification after translation in order to form the specific shape necessary for their role in the body. There are many types of modification and most of these post-translational modifications are enzyme catalysed chemical reactions is response to a specific target sequence within the protein. (Bürkle 2001, p.1533)
The most common post-translational modifications as shown in Figure 1 are N-linked glycosylation, phosphorylation and acetylation. N-linked glycosylation is the covalent addition of a carbohydrate chain to the nitrogen atom of an amino acid. This usually takes place in the endoplasmic reticulum. N-linked glycosylation usually occurs on the N4 of asparagine in polypeptide chains. (Glycosylation, 2017) Phosphorylation is often reversible and it is this ability to go back and forth which makes this modification so useful in regulation of cellular processes such as the cell cycle, growth and differentiation. It is the addition of a phosphate group and is often on threonine, serine and tyrosine amino acid residues. (Post translation modification, www.sigmaaldrich.com) Acetylation is the addition of an acetyl group (CH3CO) to an amino acid residue. The addition can be both enzyme catalysed or non-enzymatic and acetylation is often involved in the structure of histones. Much like phosphorylation, acetylation is also reversible. (Brock, 2010) Reversible modifications allow the activation and deactivation of certain proteins in order to respond to any changes in the environment as necessary.
It is estimated that the human genome is comprised of approximately 20000 genes while the estimation of different types of proteins in the body is around 1 million. The combination of post-transcriptional modifications and post-translational modifications greatly increases the proteome diversity and shows that many genes encode many proteins. (Overview of post-translational modifications, www.thermofisher.com) As shown in Figure 2, there is a large increase in complexity between the genome, transcriptome and the proteome.
Post-translational modifications can be carefully studied and analysed to study whether errors in these modifications can lead to disease. An error would lead to a dramatic difference between the resulting protein and the desired one and often would mean the protein could not complete its role in the body. The study of heart disease, cancer, neurodegenerative diseases and diabetes are all though to be influenced by the modifications of the proteins involved. With ever-improving technology we are able to study the relationships between health and disease and modifications. (Post translational modifications: An overview, 2017) When detecting adaptations, depending on the protein and modification being analysed, there are various techniques available for detection, identification and validation.
Immunoprecipitation is the basis of many post-translational modification detection assays. Antibodies are bound to a solid support and the targeted proteins within the sample interact with the specific binding sites on the antibodies. The non-targeted proteins do not bind and are later removed through various washing stages. Those that did remain attached to the antibody are then removed from the support matrix and undergo further tests to determine whether the protein had been post-transitionally modified or not such as western blot analysis or mass spectrometry. (Post-translational modification detection techniques, www.cytoskeleton.com) In silico modelling of post-translational modifications is a growing area of research and as a result, databases containing information on the types of modifications can be used to analyse trends between frequency and types of proteins which undergo modification. (Omajali, J.)
As these post-translational modification sites are so vital to protein development, when mutations occur it is believed that the malfunction could lead to various diseases. In one case, the loss of N-linked glycosylation in the prion protein leads to symptoms such as early-onset dementia and hypometabolism. Kennedy’s disease is thought to occur when there is a loss of acetylation and advanced sleep phase syndrome is thought to be linked to an absence of serine phosphorylation. As databases documenting various modifications continue to grow, there is a growing implication that mutations in post-translational modifications leads to disease. (Li, S. et al., 2009) It is known that post-translational modifications are affected by the aging process. As humans age the regulation of modifications decreases significantly causing age-related alterations. These alterations have been linked to some neurodegenerative diseases, atherosclerosis and cancer. (Santos A.L, Lindner A.B, 2017)
The highly regulated process of post-translational modification gives rise to the millions of proteins in the human body that allow such complex reactions and carefully controlled responses to stimuli. Addition of groups, cleaving bonds and associating ions to specific molecules enable proteins to perform their roles in the body and maintain a person’s health; however, mutations after transcription or translation cause the incorrect or absence of a vital modifications. This ultimately leads to the breakdown of cellular processes. As research into the significance of protein modifications furthers, more is known about how degenerative diseases are caused and what intervention could be taken to prevent disease and symptoms.