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nbme24/Block 3/Question#46 (reveal 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 k_tron_3000(34),
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The oritdscinep of abtlrliea rlowe mlib lsso fo arbtvioni ispeilm CDLM dm,aaeg dan teh estbna DsTR + Remrbgo msee ot me to eb inlmgipy taht he spoybils ahs sbeta dsailors ormf ylihissp r(o hsemngito ryev asimlir ni stpetne)nai.or

sA rof teh roteh nwrsesa, A si wgron ubaecse ish morto uitofcnn si it,cant B is onwgr aecseub apni nda tmueteraper ftesciid rae tno emi,dnteon C is wgron uebcase it ilpisem a fepsicic evren is dae,pterpn tbu he ahs tslo lartbelia nnoaiesst in hsi ineert lewor iremtisxeet

D is eth ittc,sreik dan ’Im not %010 e,usr utb I oulwd tkihn uiodhryatpcal fo eth riernaot (nrl)etva oorts owldu uacse otrmo ftcsdeii ecsin tyeh arcry tomor fenetfsr.e Yuo ghtmi asol pexcte atht tromo iyofntdsnuc to eb rluatenia,l nesic it uoldw eb lunlekiy ot aevh a obeprlm ihtw hte vener storo on hotb dses.i aosl eht CLDM si ont aodectl rnae eht ontirrea sootr fo eht lanpsi cod,r so if eht tenaoirr rotso wree tfeaecfd uoy ryalle wund’lot epxetc ot see vibotryar .slos

oS labcsiyal reoscsp of ianome,tilni I od efel liek sorsyne tneoyapurh is an leeyxetrm augev arswen ohuhtg nad I ntwas’ a nfa of eht uoi.etqns

submitted by vshummy(178),
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I ihtkn meor gyalreenl, nrpoeit ifolndg eapphns at the RER and the mset ssya eth ipnoret sneotd’ fold yepr.olrp llayfp,ieicSc teh osmt coonmm FC tioautmn is a dmfoldeis rienpto and hte netriop si aneertdi ni het RRE dna nto proentdtras to eth lelc nerbamem - AF 0192 pg 0.6

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. +18  
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!). +10  
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 +  

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:

+/- drdoom(1112),

submitted by seagull(1790),
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I vahe na iseus wiht ihst snuoeqti hchiw loas scliocftn htwi oWUd.rl nI rreod to be ddegader by pessooeomtr eth selimdodf potrien owuld ende ot be seenrpt ni het oytscol ofr .banituuion tI ti ltamacdcuue ni teh ERR ehnt how sedo it etg dgga?et lneHt,soy so

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(1112),
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Teh TFCR oreintp is a reetnasmrbnma eorpnti. ieLk lal tnopsre,i tis olniasanrtt egbins in het yo;lsoct atht ,sida RFTC ctnionas an -ursemitNn g“asinl e”s,cenequ whihc emasn sa ti is gnbei an,ltetsrda ti (nda teh oosirebm mgniak )ti! illw eb rrnstpoaetd to eht icdnpmaoEls ctu^uiml.eRonote!oft

As ti estg tan,adertls tsi ohpdyocrhbi oifstm lliw meeerg, iwchh ebedms hte FRCT ietponr iitwnh het ihipolohpsdp rbelaiy of the RE et!silf Ttah nasem the nrtoeip liwl venre gnaai be ndouf n“i eth ty”oscol uacbees it tesg edhdreat hgtourh hte eyblair hch(wi ,is in tcaf, owh lal aratsemebmnrn rosnipte mbeceo mambseanetrrn itnroesp at teh llce casrfue -- htye aveh to eb dema tnoi nrrsmenmteaba ospnrtie in eth ER ).tri!sf

So, s,ye mtya,lelitu sethe diodmefls psetnroi lliw eb ecrtided taowrd a esomeoartp rfo greyai/cgtandnocierld, tub ahtt liwl paepnh as a lletti ilvecse (or ”om;op)“lise eth edismfldo ietro,np in hsti ca,se si ont etauowl-sbler cin(,es yb tidfne,iion it ash dobhprhoyic soimtf wihhc gte tde“ehard hro”ghut a lieaybr to ceaetr eht rsbrtmenenama t,rtpn)ea wichh mesan uoy ntw’o indf it in eth .lsoocty

\ fto!ootne \ heT thchgiin of tca*evi soeobrmsi ot hte polismndcEa ucietuRml si wyh we allc atht aear of ER hurgo“ lidapmocEns lcReimuut Rr;(E)” no trcneelo csi,roycmop htat tisonec was dpeblsekce wiht eltitl ;dsot l,aetr we suh)(mna ervdcoieds thta hstee sdto wree smoeros!ib

\ * \ By ietcva“ re”soisbmo, I sutj amen ssmoorebi ni teh sopscer of itgovcnrne NRAm ot epnitro! hW(at ew acll o“tnsa”antlir );

orF a eartg ltliet muyarms of teh pcEalsonmdi culimeuRt (and amny roteh tcscpnoe in aolmrclue o,yio)bg!l ese hits from etl’srbA eclMrlauo oliBygo of hte lCel:

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(1112),

submitted by therealslimshady(37),
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nWhe eopsrnit ibegn amed in the ER ,loimsdf htye talcmceauu in hte RE, hhciw nthe grsegrti emht ot be tips uto oitn the lotyocs nad bcemoe geedddar by ot.amossepre ,suhT hte mlcuconuatia fo hte ideldmsfo npetori in het RE si udrqieer ofr temh to mteillyaut be agedgt by qiitubuin adn be eageddrd in tomaersos.ep

Eevn if yuo regau taht eyth ilwl eb ucmntgcaulai in hte sotocyl ecebasu rtmaeospseo rae in het ,tolosyc eht oiqtsuen is ganisk ewreh era eht nsopteir cuicungtmlaa, not eibgn dgredade. oS yteh ct'na ectalcuuma ni orsoamp,stee saueceb yeth rae teedoyrds ni h.emt

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(28),
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sTih is mfro aobmss: udattMe RCFT gnee (5FΔ80 )tntuimao → dlfoismde ipertno → tcdefviee enrtipo si eetaidrn ni the ogrhu pidsclonmea tclreumui (rR)E fro aoidaedtnrg → TgtAaP-de hidocler nhnacle is sbenta no eth ecll sfercau of iailelehtp ellcs hgtuturoho eth obyd ,( itsentalni and tpsirarryeo iilthea,ep swtea s,dngla ecxioren ra,snceap roxeicen gsdaln of udoieevcrprt ro)ansg

submitted by unknown001(2),
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e1thr.e rea yman nasvarit fo cyctsi iisofsbr so itsh insoqteu is not tbauo ph.psyahty of FC

p2i.otn of enqsitou : herwe dose oiretnp ondiglf courc ? sw)aner RER

  1. IN HTSI EYPT FO CF , if oprietn intso oflded rypreplo ni RER iwll it og tuo ro iwll ti amluauectc ? srena)w ti lilw meclauactu in RER.


submitted by blah_blah(1),
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flu hepl;aysshBawhIfbhG&ulctt.=yHe/wn/a:atoc=pmn3_peggX?mowNniewua/vt.Qicoblsyoju

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