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NBME 24 Answers

nbme24/Block 3/Question#46 (53.8 difficulty score)
A 15-year-old girl with cystic fibrosis has a ...
Endoplasmic reticulum🔍,📺
tags: cell_bio cell_trafficking cell_transport protein_folding 

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submitted by vshummy(166),
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I kinht moer ller,eyang eoniptr ofgdiln nphepas at hte ERR dna teh estm ssya eth itpenro nost’ed fldo .lyoprper licpeica,Slyf eth mtso mnoomc FC naoiuttm is a mfdseidlo penoirt dna hte rtionpe si naetdeir in het RRE dan tno rptosetanrd to eth ecll emeanrmb - FA 1029 gp .06

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. +16  
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!). +9  
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. +5  
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! +1  
drdoom  * By “active ribosomes”, I just mean ribosomes in the process of converting mRNA to protein! (What we call “translation” ;) +1  
wrongcareer69  How many goddamn ways are they going to test us on CF. I'm so over this! +2  
furqanka  also in FA, under alpha 1 antitrypsin, its says 'Misfolded gene product protein aggregates in hepatocellular ER". might be the same concept. +9  
joanmanuel26  According to Kaplan; All proteins that are synthesized in the ER must fold correctly in order to be transported to the golgi aparatus and then to their final destinations. If the mutation cause a misfolded protein, the result will be the loss of the protein function and, in some cases, accumulation of the protein in the ER. +1  
drdoom  @lilyo Thinking about this more. You will not find the (misfolded) protein in the cytosol. The misfolded protein may be inside a proteasome—and a proteasome may live in the cytosol—but the misfolded protein itself will never appear in the cytosol. The products of its degradation might (constituent amino acids or small peptides) but if you had an antibody for the misfolded protein and asked it “Where is the misfolded protein?”, the antibody would answer: “Most of what I could find appears to be in the rER.” +  
yesa  Check out the calnexin cycle, usually proteins that are made in the RER and misfolded get tagged and 'refolded' and then scanned again for proper folding...and if they really can't be refolded, they're degraded then and there! So the only place misfolded CFTR could accumulate if misfolded is....RER... (Link to calnexin cycle: +  
amy  FA2020 47: " Absent or dysfunctional SRP (signal recognition particle) results in accumulation of protein in the cytosol" +  
drdoom  @amy, that’s a good point but it assumes the protein is otherwise normal, i.e., not misfolded or “abnormal” in some other way +  

submitted by seagull(1683),
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I aevh na esuis twih hsti osqeinut ihhwc osal ocnlfscit thwi lW.Urod nI erdro ot be eeddrgda by oessopretmo eth moisldfde oetirpn uolwd dene to eb nerespt in eth lcooyts rfo iannotubu.i tI it duamtulaecc in eht RER tneh hwo does ti tge deg?tga slt,Hynoe os

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 +9  

submitted by drdoom(958),
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Teh FTRC opitrne si a mnernsaarbetm re.ponit ieLk all tepsnr,io sti oatlsinrnta beigsn in the losycto; ahtt ,sdai RCFT nostnica na nmNi-uerts slnig“a eeenuq,c”s wichh emsna as it is engib lstanrtdae, it (dan eht boiorems ankmig t!)i liwl be ntadpretsro ot hte pcoimEdlsna tecmluuRi.^notefot!o

sA ti gste rd,neaastlt its ryboiochhpd sofitm liwl ,emeger hwhic beemsd het TFCR nripteo wthiin eht hliioppohspd lyeriba of teh RE fi!tesl haTt emnsa het ortepni wlil enrev gnaia be donfu i“n the yto”ocls easbuec ti gest edrahdte hrtugoh the aierybl iwc(hh ,si in tfa,c owh lla saartemmrbnen sionertp mbecoe rnsanertemamb npirstoe at hte lcle rusefca -- tyeh vaeh to be dema toin tenneaambmrsr rsienpto in het ER !rs)ft.i

So, ,yse ,lutiaelmty eesht msofidedl notpreis lilw eb cdreeitd twroad a emterposoa ofr ndodrgieca/gierct,ynal tub ttha lwil epanph as a teltli eslivce ro( lmpoe“i)”os; eht eomsdlidf pio,ntre in hits scae, si ont bewes-ratullo ncei(s, yb iofntein,id it sha byhhopdicor ftsiom ihwch gte add“heter ghtu”ohr a irybale to rteeca the anrmsebtreamn t)enra,pt hicwh esnam uoy tn’ow dnif it in teh yo.otcls

\ neofot!to \ Teh inihcght of ev*itca siemoosrb ot the aipEomlscnd iuceRtuml is ywh ew lcla htta reaa fo RE hogu“r mEolscpdnai leutRimcu rE);”(R on onlctree cyipsrc,omo hatt eisntco asw cdeeeslbkp ithw telilt o;sdt ltrae, we (nhsuam) ediecdrvso tath eseth sotd eerw mbo!sisreo

\ * \ By citv“ae r”seosimob, I just neam mrossboie ni eht sosrepc fo ectigronnv RmNA ot r!inpeto ah(tW we llac “natlirstnao” );

For a gaert lilett rmumasy fo het ondcEilsamp tmlcRiueu nd(a aynm oethr epccston ni oalrmeclu )olb!y,goi ees tish mofr ’tAlbser uoealrclM loigBoy fo het Clle:

drdoom  ^ I'm just re-stating in one comment what I wrote in multiple subcomments above: +  

A mini-discussion of protein transport within the cell is here:

+/- drdoom(958),

submitted by therealslimshady(31),

When proteins being made in the ER misfold, they accumulate in the ER, which then triggers them to be spit out into the cytosol and become degraded by proteasomes. Thus, the accumulation of the misfolded protein in the ER is required for them to ultimately be tagged by ubiquitin and be degraded in proteasomes.

Even if you argue that they will be accumulating in the cytosol because proteasomes are in the cytosol, the question is asking where are the proteins accumulating, not being degraded. So they can't accumulate in proteasomes, because they are destroyed in them.

drdoom  nice catch with the “accumulating” remark! qq, when you say “triggers them to be spit out into the cytosol”, do you have a source for that? don't recall learning that anywhere myself. thx! +1  
therealslimshady  I can't remember where I read this but it stuck with me, I think it was a cell bio book +  

submitted by mutteringly(19),

This is from amboss: Mutated CFTR gene (ΔF508 mutation) → misfolded protein → defective protein is retained in the rough endoplasmic reticulum (rER) for degradation → ATP-gated chloride channel is absent on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)