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nbme21/Block 3/Question#28 (73.1 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 tnkih ti sah thnosegim ot do hitw gcleyni u(de to sit lsalm zise it nac tfi ni mayn asecpl eewrh oehrt oiamn dsica nac otn nda enceh ti rdesipov ts“alrcruut oesntsmacp”c to teh loncalg,e .i.e ptu a knik in eth laaph ilex).h If ngiycle si amdeicspl yb sotinmehg ,esel I ot’nd nktih elaopgoc-lnr nac mofr tis tecrroc ncreodays ct.esruutr

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 d,fegiur XYciyn--elg si ytnhcialcle nrdsoeidec a ymi“prra aomin diac urrutestc of a prto”eni escni hte tninidofie fo a aimPyrr usrcurtet of a eitnpro si a“ niearl nhiac fo aoinm ”dasc.i fI oyu emss itwh het rPmyrai tusreurct, sa in teh iusntoqe s,tme yuo ncnoat orfm eth oSdcerayn surtcurte of the ,neoptir hciwh si eemtrddnie by eht dnggheyi-nbronod icwhh rscouc eebtwen hte epetdpi abcbenok, epndtndneei of the R .rupsog I ohep this dmae se.nse

oFrm akpeiwdii: “dcoeanSyr eustctrru is mlfryola dfdeein by the aertnpt of nydorhge dbsno entbeew hte amion nygedohr nda yrxabocl yexngo masto in eht pediept nebbkcoa”. hisse(amp in)em

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(896),

submitted by usmle11a(77),
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ok yusg nda i tqeuo mfor bim-efre:o2htiohgtss/wce0tmeowu1wnoortt/e/

0%9" aevh na dbeiileniaft cegietn motiatnu LCO A11 and LOC A12
usecas laobnmra oneaglcl ksiorli-nsgnc aiv a iygcnle tnouitsusbit ni hte llnoacegpro lolmeceu "

whihc asnem htta OI has a ylncgei iustutsiobtn adn efoerhrt tsi nblaue ot omrf a yscdearon

submitted by hungrybox(1051),
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eDu ot ygleis'cn lalms zesi, ti rseteac ksk""in in eht nmoai idac .cesuneeq seTeh knisk ear ddeene ot ytocecrrl omfr hte oyasedrnc etsrcuru.t

rteOh raewss:n

  • aednkewe" retonitacni ewtnbee aoncllge nda oprogtn"ycela - gcelnlao + epgartlyonco = aicgtller.a hTe tqoineus tsme tonnesmi ymna tcsfdee ni OENb te(py I elcnal)og ubt no nmtenoi of destfce in OrTaWllcage e(ytp II goal)cnel

submitted by an_improved_me(18),

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(896),
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eHers’ noe awy ot erse-csmot-fplanoeii deda“erecs -hnooyenbdrgd ”nfaiomto:r ’Im nto a big afn of shit enli of orsnigna,e btu cehytcilaln ianlane sa a eisd ugrpo ahs eomr gsryhoden* orf oeilpnatt ohgrndey onbgnid tahn necigyl:

ielan:na 3—HC
en:lgcyi H—

S,o lihe”aycnlt“,c enalina dulwo rtpiem ermo -hyobnedrngdo f,rimtonoa chwih ithmg lowla uoy ot ileaientm hatt hcceio.

taTh dais, it eesms oltsam obpissemli to rleu otu utit(woh yvre ehnctiacl dwgkeelon ro msoe rpoiddve pletierxeamn )adta thta eht sllhgyit reragl naeainl edos ont amiirp enohgydr nigodnb twenbee eloanclg oeesmlcul via ritsce staapi)l( er.ecnienfert nI serpilm m,esrt escni nlnaaie si rrega,l uoy wdlou iknht ttah it smtu somehwo efenrteri htwi eth erd-dohnongnyigb ttha oucscr ithw het eyidpwlt- liyecng.

titlcry*S kaeigns,p sit’ nto hte rbunme fo ngyrhdose ubt slao the eshgrtnt of eht ioepdl htat caleitftais ohgyendr :dinnbog a ngoehdry nobud ot a oglntsry talreceotveneig eloluemc eikl uforilne lwli ae”rap“p omre psotiive ,dna st,uh bonognyrhd-de meor rytnlgso tihw a bnyrae gonxey mdraeco(p hwit a yenghrdo octneednc to crn,aob rof mlpexae.)

Ftrhuer ard:igne

  1. hqgdu:e.s/lp.nhowe/bpddmhwdmhsu/tc/i/lhwtu..ctiepuerl
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(896),

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(896),

submitted by nmb29(0),
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I itghm be hgininvektro ti t,bu H bndo iontmfroa of s'aa easkm teh cdoesrany csrruutet of eth reotpin nelg(lcao ni hsit a.c)se The lyG to laA tbsioitnutus osed tseurl ni lses H ondb tfmoaoirn, tbu of daniluidvi s'aa otn eeenwbt alcgelon oulelscem ta(th tighm be omer ofr qaeuanrrty ttcrre)usu

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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lGy si apol,r anielAn si aoonnlrp adn ryoch.ohbipd esensMis ntaoorecnvsevin mt.oiatnu eeshT AsA aehv reifftned cicalehm terpepsrio hiwhc dlae ot sdeirdtpu eonpirt gnodlif ds(aroncye cur)er.ttus Siarlim to uGl - lVa siutinbtutos ni leScik lelC .eDseais