UPR and its Consequences in Protein Maturation
Vibhuti Malik and Parth Malik
Protein translation is a very widely discussed term amongst the experts of Molecular Biology research. In fact, proteins are responsible for all the vital traits of the body. It spans the metabolic events, the chain of organ formation in a hierarchical manner and the overall concept and outcome of traversing the genetic information. Here, we will focus on the disulphide bond formation in proteins. We all are well aware that DNA gives rise to messenger RNA which then goes on to translate itself into proteins. After this event of translation, the partially ready proteins move to endoplasmic reticulum (ER) for the disulphide bond formation. This is the case only with the proteins which contain sulphur, e.g. Cysteine. The proteins are synthesized in the ribosomes as the event of translation requires energy which is supplied at the metabolic level in the form of ATP. Thereafter, they move across several intracellular vesicles and ultimately move into Endoplasmic Reticulum. The events of protein maturation that are unfolded within the endoplasmic reticulum are highly sensitive and critical. Proteins after their initial synthesis, require so many modifications before they are locally recruited for their native functions. The changes involved may be very diverse ranging from the attachment of a carbohydrate moiety to the formation of disulphide bonds.
Another major activity that happens after the proteins are synthesized involves the formation of polypeptide bonds. The trafficking of semi mature proteins in this whole cycle of events is actively supported by the molecular level proteins of endoplasmic reticulum which are famously known as chaperones. Other than this, there are some critical roles of heat shock proteins which prevent the thermal degradation and denaturation of the semi-synthesized proteins before they finally move onto perform their physiological duties. The point of focus is to understand about the chemical nature of environment inside the endoplasmic reticulum that facilitates the event of disulphide bond formation and the related post translational modifications. Endoplasmic reticulum is a very versatile organelle in the cellular structure as we all are almost aware of. The overall compartment is differentiated into two compartments, viz. rough and smooth. Each of these compartments has its role specifically defined and decided so as to deliver a specific response at the biochemical level.
Endoplasmic reticulum walls or membranes themselves are composed of specific and unique receptors that mediate the channeling of entering proteins. There is a key bioenergetic event related to final maturation of the proteins in the endoplasmic reticulum, this is known as Unfolded Protein Response (UPR). This is a very vital consequence of the improper folding of proteins within the matrix of endoplasmic reticulum or it might also be related to the non formation of the disulphide chains in the associated proteins. This is a sort of homeostatic mechanism in the body whereby the proteins if are improperly folded or not folded get deposited within the lumen (deep internal matrix) of the endoplasmic reticulum. At this point, the neutralizing tendency of the body tissues is highly critical. This is shown or expressed by the synthesis of molecular chaperones or the degrading proteolytic enzymes. This is so as the non-synthesized proteins which have accumulated within the endoplasmic reticulum need to be eliminated outside the body. If this does not happen, the stress within the endoplasmic reticulum shoots up abruptly and the response of this stress is termed as Unfolded Protein Response (UPR).
This UPR manifests itself in the form of several metabolic disorders such as cystic fibrosis, diabetes, cardiovascular complications and in severe cases ultimately the death. It is therefore of prime concern that how and when the proteins within the matrix of endoplasmic reticulum get expressed and what type of environment prevails in the lumen of endoplasmic reticulum that drives the proper synthesis of proteins. Significant studies have shown that the environment within the endoplasmic reticulum is of highly oxidizing nature, which promote the folding of proteins. In this reference, the role of antioxidants at the biochemical level is of particular interest. Antioxidants consume oxygen by scavenging free radicals. They also promote a healthy body development by preventing the oxidative stress within the body. Now how the living system does manages to regulate the contrasting balancing biochemical fates of oxygen in the tissues outside the endoplasmic reticulum and the tissues within the endoplasmic reticulum. This is so as if the activity of antioxidants becomes too much it is harmful for the body, resulting in oxidative stress. If it is too low, it will be worse as oxygen in free molecular form will oxidize the sub-cellular organelles and result in their oxidation. How does the living systems then differentiate between how, when and how much of oxygen is being required and the way it will be used up so that no metabolic scheme of biochemical activities gets distorted.
Thus, the key question that arises from above discussion is:
"Where and how much oxygen is required by the cellular organelles and that too varying with age, sex and other pathophysiological events inside the body"?
About Author / Additional Info:
I am a Ph.D scholar at Central University of Gujarat, Gandhinagar. (Parth Malik). Vibhuti Malik is an M.Pharm student working for her dissertation project at Jubilant Pharmaceuticals, Noida.