Biological complexity: misfolded protein problems (Introduction)

by David Turell , Monday, September 04, 2017, 18:56 (2637 days ago) @ David Turell
edited by David Turell, Monday, September 04, 2017, 19:02

There are defense mechanisms to handle misfolded non-function protein molecules:

https://medicalxpress.com/news/2017-09-mysterious-protein-folding-molecule-trigger-meta...

"When improperly folded molecules are encountered in cells, the unfolded protein response (UPR) is activated within the endoplasmic reticulum (ER). The ER is in charge of molecular quality control, making sure proteins, lipids and other molecules are folded properly before the cell attempts to use them for metabolic processes. Here, a master protein called grp78 is in contact with three main signaling hubs that make up the control center of the UPR.

"When an unfolded or misfolded protein is encountered by grp78, it breaks contact with those sensors and activates the UPR. The UPR then refolds or disposes of such molecules before they are shipped to the parts of the cell that need them.

"There is a wrinkle in the UPR, however. When too many unfolded proteins build up, the UPR senses that the cell has become overstressed and activates programs to recycle the cell. Yet if a number of cells experience such stress and are similarly retired, whole organs can suffer. This appears to be where the CNPY2 molecule exerts influence during the development of metabolic problems, according to experiments performed by Li and his group.

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"The investigators examined mouse cells with and without CNPY2 and isolated the PERK protein, and its downstream signaling molecule, CHOP, within them. This interestingly named PERK-CHOP pathway, which is a major enabler of liver stress when the UPR is induced, was not activated in cells without CNPY2. When they added CNPY2 back to those cells, suddenly the pathway was restored. Protein isolation experiments confirmed their hypothesis that CNPY2 and PERK interacted closely when the UPR was again induced by the drug tunicamycin.

"In addition, the master protein grp78 that regulates all three main UPR sensors interacted with CNPY2 under normal conditions. But when the UPR drug was added, grp78 left CNPY2 able to interact closely with PERK, which finally activated the PERK-CHOP pathway. Last, they found that the PERK-CHOP pathway, when activated by free CNPY2, further increased levels of CNPY2 in the liver. In other words, CNPY2 was able to further reinforce itself once activated.

"Taken together, the team's experiments showed that CNPY2 powerfully sustains cellular stress when the unfolded protein response becomes active, providing a link between the UPR and the development of metabolic problems in the liver.

Comment: Not only is the biology of the cell highly complex, it carries protections against mistakes. The normal processes and the protection for mistakes both had to be started at the same time. Since mistakes would be anticipated to occur, this implies planning and design for the entire systems. Chance attempts will not work.