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NBME 21 Answers

nbme21/Block 3/Question#28 (72.7 difficulty score)
A 1-year-old girl is admitted to the hospital ...
Disruption of the secondary structure of collagen molecules🔍,📺

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submitted by wasabilateral(41),
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I htkni it ash esimtnhgo ot od thwi ielgcny ud(e to tsi mllas zsei ti nac fti ni ymna lsaecp wheer ethro ionma sdiac nac tno dan nchee it disrevop rsuutcrt“la tmo”scaespnc to teh l,aenlgoc .i.e tpu a knki ni eth alhpa xihe.)l If lniycge si imsdepcla yb gnohsmeti se,el I odn’t tinhk lnoaceolg-rp nca omfr sit rctoecr ocsndyare

jotajota94  True! also, glycine is 1/3 of collagen alfa chains, so it makes sense that substitution with alanine (which is much bigger) would lead to disruption in the alpha helix formation. +  
jotajota94  True! also, glycine is 1/3 of collagen alfa chains, so it makes sense that substitution with alanine (which is much bigger) would lead to disruption in the alpha helix formation. +  
thepacksurvives  Glycine is small and bendy, which allows it to form the fibrils for the triple helix +  
brasel  Also in general (FA 2018 pg 50) OI is from problems forming the triple helix which is secondary structure. Fortunately, they gave us something to reason with in the question (Gly->Ala) +2  

submitted by cellgamesgojan(40),
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I efgr,iud l-g-XiyecnY is lyihncclate ioecdendrs a ymrprai“ nmaoi cdai currutest of a irno”etp nscie hte eidftninio of a imPrary suttuercr of a torienp si “a lraeni ahnic of oinam ais.dc” fI uyo smes wiht het maryPri rscu,ettru sa ni het osenqitu ts,em uoy tnnaco fmor eht ecnSodayr suurcertt of teh pt,erino cwhhi is tmeredeidn yb the gdegobyrodinnnh- hwcih ouccrs teweben hte ptdeeip kbcbanoe, epddntneien fo het R urospg. I hepo tshi maed es.esn

Frmo aiedpikiw: acenro“ySd utuctserr is malflory iddneef by eht nrpteat of odgyenrh bdnso wetnbee the imnoa yrogdneh and xoaclryb noxegy asmto ni teh pitepde koncbabe”. shpsiem(a e)mni

From Molecular Biology of the Cell:

Biologists distinguish four levels of organization in the structure of a protein. The amino acid sequence is known as the primary structure of the protein. Stretches of polypeptide chain that form α helices and β sheets constitute the protein’s secondary structure. The full three-dimensional organization of a polypeptide chain is sometimes referred to as the protein’s tertiary structure, and if a particular protein molecule is formed as a complex of more than one polypeptide chain, the complete structure is designated as the quaternary structure.

+/- drdoom(885),

submitted by usmle11a(76),
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ok syug adn i qteuo fmro lsau/pccm/tf0:oec./s/srtdee/4brhwopstri1snoewmplet-.wtthisoietei2oag

"90% ehav an eiinditbflae ietceng mniautot OL C 1A1 nad OCL 1A2
esa scu oamablrn oealclgn cisginnrkos-l via a nieygcl instubsoutit in teh plnoraeogcl meueocll "

hwich manse ttah OI ash a cgneily tuisoitbnsut dan oherrfte ist aubenl to mrof a daryconse tstrcu.euru

submitted by hungrybox(1044),
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ueD ot g'yncelis sllma ze,is it eetrsac skk"ni" ni eht onmai idca eqeusnc.e ehseT kiksn rae edeedn ot rorleycct rfom teh oserncady rectu.sutr

rOeth r:sanswe

  • ede"nawek acnnetirito enewbet leglocna adn egoarltnc"pyo - oglanlce + potocylragen = hTe useniqot etms mninseot mayn dsteecf ni NbOE ept(y I ceal)onlg ubt no ontemni fo csftede in WlcOagaTrel etyp( II eolgancl)

submitted by an_improved_me(16),

ANother way to get at it is via elimination:

A. hydrogen bonding wouldnt really change since neither alanine nor glycine are polar B. Gly > Ala shouldn't change how proline is modified (I mean it COULD, if there was a steric hindrance or something, but not a great answer) D. nothing to indicate that collagen degredation is altered in response to an AA substitution. Also, in the context of OI (which is the presenting complaint), we already know that the problem doesn't have anything to do with degredation, more with the change in structure/function E. Honestly don't know.

submitted by drdoom(885),
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reHse’ neo awy ot nl-iretfosesei-mocap edcaersed“ bydonhdngo-re m”:fatnioor I’m ton a igb nfa fo this elni fo rsgan,enio ubt calynlchiet aanenli sa a sdie gurop hsa oerm grsedhny*o rof oiapntetl yogrhnde idnnbgo ntha eyiglnc:

l:eanani 3C—H
g:yecnli H—

o,S a“h”nctllec,iy niaaenl uldow prmeit oerm boddorng-enhy ftaimon,or hihwc tmhig oalwl uyo ot mlaetenii thta heioc.c

ahtT ,adsi it seesm aoslmt mosieblpsi to uerl uot t(owituh eyrv celtihcna kwelogedn or emso dpeoirvd xlepneraeimt daa)t hatt eth ihlgsytl grarel lineana oeds ont airmip hdngeroy bngoind twbeeen onelalgc uemlocesl aiv icesrt pi(saal)t neecet.firner In plremis mse,tr iscne ilnnaea si rlgae,r yuo dluwo inhtk htat it msut mwohose eefiretnr ihwt hte hg-onbreidnogydn htat orucsc ithw eht t-eiywdlp ycigeln.

citryl*St aeg,knips t’si not het uemrnb of ehnsgdyor ubt sloa teh gsrnthet of the lpideo ttha slfateiacit hrndgyoe nbngo:id a rogendyh oubdn to a lysontrg ercoeattngvleie uoclelme eikl euirofln lwil p“p”arae ermo sitiovpe n,da ths,u egnno-brdyohd ermo yolrsntg iwht a nraybe geyxno ae(dpcomr iwht a nodgehry ontcendce to ncoar,b ofr .p)xaleem

hutrFer gadn:eir

  1. /mw/l.wp/:hthn.edhiqtmith/uuhdseuel/.dpdcbglus.wecrop
hungrybox  Appreciate the effort but this is far too long to be useful. +26  
drachenx  hungrybox is a freaking hater +  
drdoom  @drachenx haha, nah, coming back to this i realize i was probably over-geeking lol +  
blueberrymuffinbabey  isn't the hydrogen bonding dependent on the hydroxylated proline and lysine? so that wouldn't really be the issue here since those aren't the aas being altered? +  
drdoom  @blueberry According to Alberts’ MBoC (see Tangents at right), hydroxylysine and hydroxyproline contribute hydrogen bonds that form between the chains (“interchain”, as opposed to intra-chain; the chains, of course, are separate polypeptides; that is, separate collagen proteins; and interactions between separate chains [separate polypeptides] is what we call “quaternary structure”; see Tangent above). And in this case, as you point out, the stem describes a Gly->Ala substitution. That seems to mean two things: (1) the three separate collagen polypeptides will not “pack [as] tightly” to form the triple helix (=quaternary structure) we all know and love and (2) proline rings will fail to layer quite as snugly, compromising the helical conformation that defines an alpha chain (=secondary structure; the shapes that form within a single polypeptide). +  
tadki38097  also you can't H bond with carbon, it's not polar enough +  

From Molecular Biology of the Cell:

Hydroxylysines and hydroxyprolines are infrequently found in other animal proteins, although hydroxyproline is abundant in some proteins in the plant cell wall. In collagen, the hydroxyl groups of these amino acids are thought to form interchain hydrogen bonds that help stabilize the triple-stranded helix. Conditions that prevent proline hydroxylation, such as a deficiency of ascorbic acid (vitamin C), have serious consequences. (Emphasis mine)

+/- drdoom(885),

From Molecular Biology of the Cell:

The primary feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains, called α chains, are wound around one another in a ropelike superhelix (Figure 19-43). Collagens are extremely rich in proline and glycine, both of which are important in the formation of the triple-stranded helix. Proline, because of its ring structure, stabilizes the helical conformation in each α chain, while glycine is regularly spaced at every third residue throughout the central region of the α chain. Being the smallest amino acid (having only a hydrogen atom as a side chain), glycine allows the three helical α chains to pack tightly together to form the final collagen superhelix (see Figure 19-43).

+/- drdoom(885),

submitted by nmb29(0),
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I hgtim eb ntinkvgerhio it bt,u H donb tifomnora of s'aa smkea teh ryaosedcn tsrcuertu fo teh pritneo alcnleo(g ni isht .es)ac hTe lGy to laA nttiiutssubo dsoe tsurle in slse H dobn maintroo,f tbu of ilviadindu 'asa otn weenebt oellncga elcuomsle ttha( ihmtg be emro rof ueatarnyqr urstutrc)e

lpp06  I think the key is in the answer phrasing, the answer mentioning H-bonds says "Disruption of H-bonds between collagen molecules" Although collagen does undergo H-bonding to support the triple helix, this is done within the same collagen molecule. Linking different collagen molecules occurs via the lysine - hydroxylysine links done in the ECM +1  
kevin  this is the one comment that finally helped me understand why that was incorrect. thank you +  

submitted by basic_pathology(12),

Gly-X-Y is backbone for collagen alpha chain. 3 collagen alpha chains spiral to form triple helix. Glycine has no R group, allowing for flexibility and formation of triple helix. No glycine prevents this continuous spiraling, preventing the formation of collagen secondary structure.

Recall that alpha-helices and beta-sheets are examples of secondary structures. This can be thought of a manifestation of the alpha helix.

submitted by j123(8),

Primary structure = amino acid sequence Secondary structure = structure formed with a single amino acid sequence (beta pleated sheet, alpha helix, etc) Tertiary structure = multiple secondary structures interacting together (multiple beta pleated sheets stacked on top of each other, etc) Quarternary structure = protein structure formed from folding of all tertiary structures to make binding sites, etc.

Since the alanine was put in place of the Glycine, the primary structure was unable to form an alpha helix since alpha helix structures need a particular sequence (gly - x- y) in order to form hydrogen bonds to keep the helix stable.

submitted by lilmonkey(19),
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ylG si poa,rl lnaAine si rnlaopon nad hrbciphy.ood nsiesMes ncvvosoeetrnian attmniuo. heeTs sAA vaeh rdfeeiftn hialcmec ioppererst iwhch dlea to sdireptud rntopei fnoligd (oansdyrce utr.ctus)re Sraliim to luG - laV iobutsnittsu in liecSk leCl sD.eseia