Question

+ 125% Zoom W Add Page M Insert ul T Chart Text Table = Shape Media Comment Diverse and delicate mechanisms maintain cytoplasmic and organellar proteostasis. Answer following questions. (2 X 10 points = 20 points). 1. Molecular chaperones (heat shock proteins, HSPs) play key roles in proteostasis. How do molecular chaperones regulate (1) activation of HSF1 (a transcription regulator of HSPs), and (2) unfolded protein response (UPR) in the ER? 2. ATFS-1, OPA1, and PINK1 are molecular factors involved in mitochondrial quality control. (1) Define "mitochondrial quality control" and (2) describe how ATFS-1, OPA1, and PINK1 are regulated to control mitochondrial quality.

Answer 1

1. The proteostasis is defined as "Control over the protein folding, trafficking or regulation in various mechanisms in the activated and functional form"

a. Sometimes the protein is misfolded or the trafficking does not take place in the proper way which disturbs the static condition and stress started building upon the cell. So to remove out such stress condition the molecular chaperon comes in a picture. The chaperons work under various conditions and generally in protein folding. In case of the heat like stress, the heat shock chaperons (HSP) play a critical role under the regulation of the Heat Shock Factor 1 (HSF-1). This is the transcription factor that has a DNA binding domain that helps binding to the DNA and thus helps to transcribe and further translate the open reading frame which is responsible for the activated pathway of the HSP which brings the proper folding of the unfolded protein.

b. In some cases, the protein folding does not take place properly due to the lack of chaperon signaling or the accumulation of the proteins. The protein folding of misfolded protein takes place in the Endoplasmic reticulum and thus whenever the unfolded protein comes in the picture it leads to developing the following conditions:

• Accumulation of the unfolded protein in place of the folded protein and thus inhibit the translation and refolding of protein to gain the functional form by the molecular interactions
• The unfolded protein might run the degradation pathway as to degrade the protein content in the ER and thus help the cells to skip the pathways involved in this reaction
• It can also activate the chaperon production mechanism which will develop the molecular folding machinery "chaperons" which will help to fold back the protein.

2. Mitochondrial quality control is the mechanism of keeping the mitochondria working or function. The organelle can keep functional only if it has been provided with the properly folded proteins and thus allow to maintain its integrity. In the case of the mitochondria, such functional integrity is maintained by some factors which help in the production of proteins which will take part in the maintenance. This is the transcription factors which will lead to the unfolded protein responses in the mitochondria:

• Mitochondria are made up of outer and inner membranes in which the OPA 1 transcription factor plays a role to build the proteins for maintaining the inner membrane of mitochondria with the proper components.
• In the case of maintaining the inner membrane, some transporter has been fitted in that membrane structure and thus the PINK 1 helps in the import of protein molecules inside the mitochondria and if the PINK-1 has been mutated the mitochondria start aggregating with the increasing of the age.
• ATFS- 1 is uniquely suited for the communication of mitochondria with the nucleus as it contains both mitochondrial and nucleus signaling molecules which can direct the protein to the mitochondria as well as nucleus based on the need of transport. It allows the protein to accumulate in the cytoplasm and then helps in the trafficking of respective proteins.