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nbme24/Block 3/Question#46

A 15-year-old girl with cystic fibrosis has a ...

Endoplasmic reticulum

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submitted by vshummy(82),

I think more generally, protein folding happens at the RER and the stem says the protein doesn’t fold properly. Specifically, the most common CF mutation is a misfolded protein and the protein is retained in the RER and not transported to the cell membrane - FA 2019 pg 60.

uroosisyed5  Which makes sense if we think about the pathophys of elevated Cl- and Na intracellularly. Both of these ions go up inside the cells due to the retention of the misfolded proteins in the RER. +  
lilyo  I actually disagree with this reasoning. The pathophysiology in CFTR is not due to accumulation of misfolded proteins. It is due to decreased/absent ATP gated transmembrane Chloride channel. According to Uworld, the miscoded protein is detected by the Endoplasmic Reticulum. The abnormal protein is targeted for destruction by the proteasome and never reaches the cell surface. There is NO retention of misfolded protein, there is degradation of misfolded protein and therefore absence of chloride channels on the membrane. This is what leads to impaired removal of salt from the sweat as well as decreased NaCl in mucus. I dont think the answer should be ER. Can anyone tell me if I am missing something here that makes the answer ER as opposed to cytoplasm? Because the way I see if is misfolded proteins go form the ER into the cytoplasm to reach the proteasome and then be destructed. Uworld questions ID are 805, 802, 1514, and 1939. +1  
drdoom  @lilyo The CFTR is a transmembrane protein. Like all proteins, its translation begins in the cytosol; that said, CFTR contains an N-terminus “signal sequence”, which means as it is being translated, it (and the ribosome making it!) will be transported to the Endoplasmic Reticulum.^footnote! As it gets translated, its hydrophobic motifs will emerge, which embeds the CFTR protein within the phospholipid bilayer of the ER itself! That means the protein will never again be found “in the cytosol” because it gets threaded through the bilayer (which is, in fact, how all transmembrane proteins become transmembrane proteins at the cell surface -- they have to be made into transmembrane proteins in the ER first!). +2  
drdoom  @lilyo (continued) So, yes, ultimately, these misfolded proteins will be directed toward a proteasome for degradation/recycling, but that will happen as a little vesicle (or “liposome”); the misfolded protein, in this case, is not water-soluble (since, by definition, it has hydrophobic motifs which get “threaded through” a bilayer to create the transmembrane pattern), which means you won’t find it in the cytosol. +  
drdoom  ^footnote! : The movement of active* ribosomes from the cytosol to the Endoplasmic Reticulum is why we call that area of ER “rough Endoplasmic Reticulum (rER)”; on electron microscopy, that section was bespeckled with little dots; later, we (humans) discovered that these dots were ribosomes! +  
drdoom  * By “active ribosomes”, I just mean ribosomes in the process of converting mRNA to protein! (What we call “translation” ;) +  


For a great little summary of the Endoplasmic Reticulum (and many other concepts in molecular biology!), see this from Alberts’ Molecular Biology of the Cell: https://www.ncbi.nlm.nih.gov/books/NBK26841/#A2204

+/- drdoom(354),


 +2  upvote downvote
submitted by seagull(714),

I have an issue with this question which also conflicts with UWorld. In order to be degraded by proteosomes the misfolded protein would need to be present in the cytosol for ubuination. It it accumulated in the RER then how does it get tagged? Honestly, so conflicted...

sajaqua1  So ordinarily a misfolded protein does undergo ubiquitination and proteolysis. It is noteable that CFTR misfolding doesn't even allow it escape the ER, so it accumulates in the ER +5  




 +1  upvote downvote
submitted by drdoom(354),

The CFTR protein is a transmembrane protein. Like all proteins, its translation begins in the cytosol; that said, CFTR contains an N-terminus “signal sequence”, which means as it is being translated, it (and the ribosome making it!) will be transported to the Endoplasmic Reticulum.^footnote!

As it gets translated, its hydrophobic motifs will emerge, which embeds the CFTR protein within the phospholipid bilayer of the ER itself! That means the protein will never again be found “in the cytosol” because it gets threaded through the bilayer (which is, in fact, how all transmembrane proteins become transmembrane proteins at the cell surface -- they have to be made into transmembrane proteins in the ER first!).

So, yes, ultimately, these misfolded proteins will be directed toward a proteasome for degradation/recycling, but that will happen as a little vesicle (or “liposome”); the misfolded protein, in this case, is not water-soluble (since, by definition, it has hydrophobic motifs which get “threaded through” a bilayer to create the transmembrane pattern), which means you won’t find it in the cytosol.


\ footnote! \ The hitching of active* ribosomes to the Endoplasmic Reticulum is why we call that area of ER “rough Endoplasmic Reticulum (rER)”; on electron microscopy, that section was bespeckled with little dots; later, we (humans) discovered that these dots were ribosomes!

\ * \ By “active ribosomes”, I just mean ribosomes in the process of converting mRNA to protein! (What we call “translation” ;)

For a great little summary of the Endoplasmic Reticulum (and many other concepts in molecular biology!), see this from Alberts’ Molecular Biology of the Cell:
https://www.ncbi.nlm.nih.gov/books/NBK26841/#A2204



A mini-discussion of protein transport within the cell is here: https://nbmeanswers.com/exam/nbme21/742#257

+/- drdoom(354),