Question

Explain in your own words what happens to improperly folded proteins in the ER. How does the cell respond when there is a couple of misfolded proteins in the ER? What happens when there are many misfolded proteins in the ER and its protein-folding capacity is exceeded? Explain in your own words using what you learned in class.

Answer 1

The answer to your query is as follows:

Sometimes protein folding involves some errors and affects the health and the functioning of the cell. When proteins do not fold properly in their functional and active state, it leads to the formation of unfolded or misfolded proteins. These misfolded proteins are unfavorable and create a barrier to the crowded cellular environment. Research has shown that the accumulation of misfolded proteins plays a key role in various neurological diseases like Alzheimer’s, Parkinson’s and Huntington’s diseases.

ER-associated degradation (ERAD) is a mechanism that helps in the degradation of most of the misfolded proteins that are found in the endoplasmic reticulum (ER). Many misfolded proteins do not have ER exit signals and they remain in the ER. They are degraded by ERAD association inside the ER. Some of the misfolded proteins which have intact ER exit signals are engaged by ERAD association machinery. It dislocates the proteins and leads to their proteasomal degradation.

Endoplasmic reticulum has some specific system that determines the high concentration of unfolded or misfolded proteins inside it. When the load of the misfolded proteins is too high, ER generates a response to remove the harmful effects of the misfolded proteins and also removes the misfolded proteins from it. It is done with the help of two systems namely, chaperons and proteasome. The ER has three sensors in its membrane that detects the misfolded proteins. They are as follows:

• IRE1
• PERK
• ATF6

The sensors are activated when the level of unfolded proteins becomes too high.

Chaperones help the misfolded proteins in the folding process. They provide a god opportunity to the misfolded proteins to refold properly. Misfolded or unfolded proteins have exposed hydrophobic domains. These domains are hidden in properly folded proteins. Chaperons bind to the hydrophobic domains and prevent them from aggregating.

Misfolded proteins are also treated with the help of the proteasome. Proteasome digests the proteins and breaks them into small fragments which are the amino acids of the proteins.

The sensors in the ER works as follows:

1. The chaperone BiP binds to the misfolded proteins. When the ER senses the high concentration of misfolded proteins, the amount of BiP reduces.The sensors dimerize or they can also leave the ER.

2. The active sensors of the ER generate different types of responses.For example, PERK inhibits the process of the translation of proteins. Thus, it reduces the amount of protein that enters the ER. IRE1 and ATF6 helps in the activation of some genes that codes for the chaperones and the enzymes required for the biosynthesis of the lipids. It helps in increasing the amount of ER so that it can handle the load of unfolded proteins.

Hope it helps!