L11 Trag Prots To Mems And Organelles Flashcards Preview

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MITO see table.

-Pyruv DH defic- enz norm forms aCoA from Pyruv. If defic then build Pyruv so incr lactate= neurol probs.
Mut art to pro= decr upt to mito- R not recog targ specif seq as Pro not us in alpha helix- is helix breaking= de stabil helix N-MTS. Loss basic resis on Phillic face of amphip helix.



-mut NLS=dis.
Sawyer synd- los/mut NLS in sex determ reg Y. SRY TF prot. Genet XY, outwardly fem. SRY req for testis diff.
LM dysphasia- Arg to cys NLS of SHOX TF= loss charge. Short stature. Skel dev.



-mut R for subset perox enzs=rhizomelic chondrodysplasic punctata.


LO1: overview sec path in mamm.
LO2: contr regul and constit sec pathways.

-constit constant.
Regul- endoc sec horm. Exoc sec dig enz. Neuron sec neurot.
-sec path in pol sec cell eg panc acinar. Sec apical only. Golgi next to nuc, lot RER.
Sig seas N termin secretory prots. Pre=sig still att.
-co transl transp- N sir expos as synth. SRP binds and stops transl. To SRPR in ER mem, GTP bound incr affin= open, GTP hydrolases and prot delivery to chann. Sig peptidases in ER mem cleaves, transl contin until ribos off and prot fold.
-insert to ER mem req for deliv mem prots destined for PM or int mem of sec path.
Int mem of sec path Eg T1 mem prot at ER eg EGFR. Deliv by SRP then sig cleaved and transl to lumen. Transl into lumen stopped at 20-25 phobic AA and anchor to mem (stop transfer anchor seq). Prot leaves translocator, synth contin in cytop til STOP. Ribos leaves. C termin stays in cytop.
-ER funcs- insert prots to mems. Specif proteolytic cleavage. Glycosylat. Form S-S. Proper prot folding. Assemb multi su prots. Hydroxylat selected lys and pro.
-post transl modif within the sec path-
Collagen- constit sec. Lot modif- corr sec and assemb.
Insulin- regul sec. Proteolytic cleavage.
-constit contin- unregulated mem fus on exoc. Eg Ig, albumin, pro hormones, fibronectin, laminin, Rs.
Regul- intracell sig path= regul mem fus of sec vesic, trigg by eg horm/neurot. Eg glucagon, beta endorphin, ACTH, alpha MSH, beta lipotropin, trypsin.


LO3: list prot modif in ER and Golgi.

-GLYCOSYL IMP- corr fold, prot stabil, interac other molecs, defic N linked Glycosylat= congenital disorders of glycosylat.
- n linked glycos- surg added to asparagine amino grp. Reqs consensus seq asparagine-X-ser-threonine.
Oligosacc assemb in ER on mem bound lip (dolichol) then transf to asparagine s/c. Oligosacc s/c modif lot in ER and Golgi by add/rem surg.
-peptidyl prolyl isomerases- accelerate inter conv Cis and trans isol of Pro- rotat arnd pep bond. Req dur fold of eg IgGs. Facil rap prot folding.
-S-S FORMAT- oxid SH of 2 cys. Imp of hold su and corr fold.
Prot disulphides isomeras- oxidised PDI with S-S accepts H from reduced substrate with SH. = reduced PDI with SH and oxides substr with new S-S bond. PDI is eg of resid ER prot, how not sec? See table.
-folding probs- prot trap in misf conf. Prot mut causes misf. Prot incorr assis other su's.
ER chap prots try to corr-
BiP-binding Ig prot- exposed AA norm buried.
Calnexin and calreticulin- oligosacc on in compl fold prots.
Retain unfolded in ER. Monit extent of unfold- if lot= unfolded prot resp- med incr transc of chap, decr transl gen.
If misf can't be corr- prot ret to cytos for deg. Prot accum to tox levs in ER= dis, can be due to 1bp mut.
Misf= dispos= insuff func prot eg alc, DM, CF.
misf=reten= incr tox/ decr func eg Parkinson's, liv fail, heart fail.



-Cis Golgi network. To Golgi stack: cis/medial/trans cisternae= sug s/c modif by add/rem. Then trans Golgi netw.
- prots go from ER to Golgi. Then sorting- P of oligosacc on lysos prots, rem Man, rem Mad and add GlcNAc, add Gal, add NANA, sultation of tyr and carbs. Then sorting to lysos or PM or sec vesics.
-sorting to lysos- lysos enz P added to OH of mannose C6= mannose 6P. Eg lysos hydrolases has N linked oligosacc with mannose 6P att.
Reqs 2 enz: N acetyl glucosamine P transferase- 3D sig. P diesterase adds P.
Overall- UDP-GlcNAc and lysos enzs use ATP to form UMP+ GlcNAc+ M6P tagged enz.
I-cell dis fatal inherited. Defic P transferase= lysos bloated with undegraded mater. Hydrolases not deliv corr.
-P add to mannose in cis Golgi. Binds M6P R in trans Golgi netw= init clathrin coat format. Pinch off =R dep transp. Uncoat and fuse late endos, lysos enz dissoc R, P rem and R recyc. Late endos forms lysos.
-O linked glycosylat- att sug to OH on ser/threonine. Imp in pg's. Compon of ECM and mucous secretions.


LO4: desc struc of triple str Coll helix and overview Coll synth.

-30% of bod prot. Most in CT- tend, lig, cartil, bone. And loose CT- struc to int organs.
-Coll synth- sec prot prod by fibroc in CT. loose CT below basal lamina conts- L+BV, RBC, elastic fib, fibrob, pg, Coll fibres.
-Coll fibres- basic unit- tropocollagen. 300nm rod shaped prot. 2 alpha chains, each 1000aa. Small glycine ev 3rd posit (gly-X-Y)n, imp for pp assemb. RH triple helix. Stabil by H bond btw chains. 1.5nm wide. Triple helix non extensib/compressib= high tensile str. Mostly Pro of hydroxyPro in X and Y posits (alpha chains NOT alpha helix!).
Diff chains combines= diff funcs at diff locat. T1 90% in tend/bone. T2 cartil. T3 CVS reticulin. T4 basal mem. T5 skin. Can form in cell, need assemb outside. Modif and assemb v regul.
-Coll synth and modif in ER- sig pep cleaved as ent ER= prepro alpha chain to pro J chain. Hydroxylat pro and lys. N linked oligo to asparagine. add galactose to hydroxylysine aid inter chain interac.
-Prolyl hydroxylase= proline and 2oxoglutarate form 4 hydroxyproline and succinate and co2. Uses O2, Fe, ascorbate. Prolyl hydroxylase assoc PDI in ER. Allows incr H bond to stabil triple helix by extra OH. Temp stable. Scurvy due to weak tropocollagen triple helix. N and C termin propep not inv in triple helix when folds.
-still in ER- chain align and S-S form stabil C termin. Helic forms N to C. 150 extra N AA NOT form helix- regul assemb. 250 C termin AA not form helix.
-procoll sec- compl O linked oligosacc chains by add gluc to galactose. Transp vesic to exoc= tropocollagen outside ER, rem N and C propeps= procoll to tropocollagen by procoll peptidases. EXTRACELL!
-format Coll fib- Lat assoc Coll molecs. Then cov X link= aggreg fibrils.
X link tropocollagen- Lysyl oxidase cov links 2 lys on diff tropocollagen= aldehyde derivs form (?spont) aldol X link. Lysyl oxidase extra cellul- reqs vit B6 and Cu, forms cov X links.
-Ehlers danlos- mut in Coll T5 or Lysyl oxidase defic.
-Coll banding- light stain no overlap Coll molecs. Heavy metal stain in gaps.


LO5: role proteolytic proc in format imp sec prots.
LO6: outline format mat insulin.

-insulin proc in ER and sec vesics-
S-S form in ER: 2 inter chain, 1 internal= specif fold stabil.
Post Golgi: connecting pep rem=compl 2 chain insulin molec.
-proteolytic proc of insulin reqs 3 enzs- pro insulin at start. PC3 endoprotease and PC2 cleave mid C pep. Carboxypeptidase cleaves out 2 Arg= mut 2 peps S-S.
Proteolytic proc after bud from trans Golgi netw. Prolinsulin in immat sec vesics. Insulin in mat.
-proteolytic proc can be v complex and yield diff prods, because diff amnts proc enzs at diff locats eg pit lobes.
-why proteolytic proc comm in sec path- can=small prots too short to ent ER via co transl. Some sec prot eg hydrolytic enz would be destruc is activ in cell. Multip bio active prods from same pp. avoid activ insulin R in sec pathway.


Prot sorting

-all prot synth begin in cytos.
Ribos att ER mem and co transl insert new prot IF prot destined for mem or sec pathw.
Robs rem cytos IF prot detained for cytos of post transl import to organelle.
- reqs for sort- intrinsic sig. R recog sig and direc to corr mem. Transloc Mach- us to X mem if destined for organelle, uses energ.