Protein is an essential macronutrient which plays a significant role in our body, including the growth and repair of tissues. Post-translational modifications of protein are a major source of modification in protein and places where their study can lead to many benefits like identification of novel pharmacological targets, drug discovery and development and understanding biological functions.
Among these modifications, phosphorylation, acetylation, glycosylation, sumolyation&isoprenylation are being widely studied. The purpose of a blog about Which Modification Is Most Closely Linked To Protein Degradation?
Ubiquitination
Ubiquitination, the enzymatic attachment of ubiquitin to proteins, is the process most closely linked to protein degradation. Ubiquitination is so closely tied to protein degradation in part because the ubiquitin itself is a signal for protein degradation.
When a protein is tagged with ubiquitin chains, it is targeted for destruction by proteasomes, large complexes found in all eukaryotic cells that are responsible for breaking down proteins with specific signals attached to them.
Additionally, many of the E3 ligases that attach ubiquitin to other proteins are themselves regulated by damage or stress signals. For example, when cells are under oxidative stress from reactive oxygen species like H2O2, one common E3 ligase called pVHL becomes activated, leading to the degradation of its target proteins. Thus, both ubiquitination itself and its downstream effects on protein degradation are increased when cells are under stress.
Phosphorylation
Phosphorylation, the addition of a phosphate group to a protein, is a process that’s central to many cellular functions. Our body is able to control the activity of proteins by controlling phosphorylation.
One of the ways we accomplish this is through enzymes called protein kinases, which are in charge of adding a phosphate group onto their target proteins. There are also enzymes called phosphatases that remove these phosphate groups in order to stop or reverse the effects of phosphorylation.
The balance between these two processes determines whether a protein will be active or not. And since so many proteins are involved in cell growth and division, making sure that we control levels of phosphorylation is crucial to preventing cancer and other diseases.
One disconcerting fact about phosphorylation is that it seems to be closely related with protein degradation. Proteins are constantly being synthesized, modified by phosphorylation, and then targeted for degradation by proteasomes—and all of these things happen at different rates for different proteins.
We know that when you increase the level of phosphorylation on a protein, it can decrease its lifespan; but we don’t know if this decrease in lifespan is simply because the protein has become more active and used up more quickly.
Acetylation
Acetylation is one of the most common, and best-understood, protein modifications. It is also, according to a recent study, the modification most closely linked to protein degradation. The study’s findings suggest that acetylation acts as a signal for ubiquitination, which marks proteins for degradation by proteasomes.
The researchers used a modified form of the green fluorescent protein (GFP), which they called GFP-BAC. They discovered that when this modified GFP is acetylated at lysine 214, it becomes an efficient substrate for ubiquitin ligases and is rapidly degraded in cells as well as purified ubiquitin ligase assays. While other modifications have been linked to protein degradation, acetylation at lysine 214 appears to be the most direct link between modification and degradation; other modifications appear to be more complicated.
The study provides new insights into the regulation of ubiquitin ligases and the role of acetylation in protein degradation.
Proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Protein catabolism is the breakdown of proteins into amino acids and simple derivatives for transport into the cell through the plasma membrane. Cellular proteolysis occurs in three different cellular compartments: in the cytosol, proteasome, and lysosomes.
Protein degradation as a part of protein turnover is necessary for many cellular processes such as cell cycle progression, removal of abnormal or unnecessary proteins, regulation of enzyme activity and signaling networks.
Ubiquitin-proteasome pathway (UPP) is responsible for the degradation of most short-lived and abnormal proteins. The N-end rule pathway targets proteins for degradation when they contain one or more destabilizing N-terminal residues. Lysosomal proteolysis targets soluble cytoplasmic proteins as well as membrane-bound organelle proteins following their delivery to lysosomes by specific receptors.
Protein degradation may be considered a subfield of proteomics because it is often used to identify new regulatory mechanisms through global analyses of protein turnover in cells treated with drugs that perturb signaling
Glycosylation
Glycosylation is the most closely linked to protein degradation. Glycosylation is the process of adding sugars to proteins or lipids. Glycosylation occurs in response to a number of stimuli, including stress and nutrient availability. In humans, glycosylation is primarily a function of the liver, though it can also occur in skin cells and epithelial cells. This process has been linked to a variety of health problems, including cancer and diabetes.
Glycans are attached to the surface of proteins by enzymes called glycosyltransferases. These enzymes work by transferring the carbohydrate from one molecule to another molecule that has an available glucose site.
Glycosylated proteins can be found on cell membranes and within cellular organelles such as mitochondria. In addition, some proteins are not glyco-sylated but still contain other types of carbohydrates (e.g., mannose residues) that may play a role in their function or activity (i.e., protein folding).
Last Words
The two types of modifications that best correlate with proteins being targeted for destruction are ubiquitination and glycosylation. Modifications of the N-terminus proteolysis, oxidation, and nitrosylation are also possible mechanisms of protein degradation.