Molecular biology is a fascinating subject to engage in because of all the various functions that fall under its umbrella.   Everything that we feel in our bodies – if you are sick, tired, or hungry, for example – is ultimately a cause/effect of some kind of interaction that occurs in our cells.   How does this work, then?   It starts when our DNA is transcribed by internal cellular machinery into mRNA.   Further mechanisms then translate the mRNA into a protein, which the cell recognizes and directs to wherever it should go.   Once in position, proteins make up the physical structure of each cell and coordinate and control all the numerous vital functions.   One of the main mechanisms for how proteins exert this control is through a process called post-translational modification.

What are Post-Translational Modifications?

Any kind of biochemical change that occurs on a protein can be considered a post-translational modification (PTM). This can include certain chemical groups or small molecules being added to or removed from specific amino acids, being cleaved into multiple constituent parts, or other actions. This process is generally carried out by specialized enzymes, or proteins with a defined set of specific substrates and regulatory mechanisms. Some of the most common PTMs include phosphorylation, acetylation, methylation, glycosylation, and ubiquitination. In general, these serve to increase the functional diversity of the protein, turning each one into a “Swiss-Army Knife” that allows it to participate in multiple cellular pathways depending on the overall need.

On/Off Switch

The most well-known role of PTMs is their ability to facilitate rapid cellular changes by altering protein activity and function. For example, phosphorylation (the addition of a phosphate group to Serine, Threonine, or Tyrosine) of a single site can switch a protein from inactive to active.   Acetylation (a modification that occurs on Lysine or Arginine residues) helps regulate binding to DNA, which in turn can influence how much of a particular protein is made and when. These subtle conformational changes to its structure are sufficient to induce the protein to function differently.

Example of the phosphorylation post-translational modification. Due to the enzymatic activity of a kinase, a phosphate group is added onto an inactive protein (released from the hydrolysis of ATP), making it active.

Crossing Guard

Protein localization is crucial for its proper function within the cell. Certain PTMs act to direct proteins to specific cellular compartments or guide them along specific transport pathways. This ensures that proteins reach their designated locations and execute their functions in the right context.

Arbiters of Stability

PTMs also play a pivotal role in regulating the lifespan of proteins within the cell. Some PTMs help stabilize proteins and prolong their half-lives, thereby safeguarding critical components from rapid turnover.   Another PTM called ubiquitination (the ligation of a protein called ubiquitin) marks target proteins for proteasomal degradation, a key mechanism for maintaining cellular homeostasis.   Ubiquitin was named appropriately as it is found in virtually all types of cells.   Being highly conserved across a variety of species from yeast to plants to human, ubiquitination is also expected to be one of the earliest developed forms of post-translational modification in eukaryotic organisms.

Basic flow diagram of how a protein substrate is targeted for proteasomal degradation by ubiquitination.

PTMs and Disease

Cells orchestrate a complex interplay of PTMs within signalling cascades, and the modification of one protein may be entirely dependent on the modification state of another.   Some proteins have hundreds of possible different modifications that can occur, which may involve multiple sites and PTM types at once, or even a single site being modified with different PTMs depending on the situation. This creates an intricate regulatory network with multiple layers of sophistication that exerts a fine-tuned control of cellular processes.   It goes without saying that with this complexity and interconnectedness also comes risks.   Anything going wrong at any step – whether due to inherited traits or a fresh mutation that occurs – can have widespread implications leading to cellular dysfunction and/or disease.   There are many drugs that attempt to stop the action of certain targets based on information showing they are not performing correctly within a certain framework.   Proteins can have multiple functions, however, and a mutated site that affects its activity in one pathway may have no bearing on how the same protein acts in a different pathway.   We also still have much to learn about exactly what PTMs are present under all the various possible conditions and how this affects activity locally, cell-wide, and in the body as a whole.   With this complexity in mind, it is easier to understand why many current drugs on the market have long lists of side-effects.   Hopefully, future advances in personalized medicine will allow us to diagnose and treat abnormalities more precisely at the source.

Antibodies and PTMs

Due to the significant role of PTMs in the modulation of cellular processes and disease, there is much interest in understanding how proteins are regulated via this mechanism. Biosynth scientists have decades of experience in making PTM-specific reagents, and can create custom antibody tools against a variety of different modification types.   Utilizing our extensive knowledge in this realm will lead to the best chance of success for your projects, and may potentially open new paths for your research.

See our biologics capabilities     https://www.biosynth.com/biologics