Secretory Pathway Flashcards
(105 cards)
components of endomembrane system
endosome, nuclear membrane (extension), lysosome, golgi, ER with ribosomes, plasma membrane
nuclear pores
proteins in, mRNA out outer nuclear membrane IS continuous with ER - fold around at nuclear pores, transcription factors in and mRNA can leave, NOT protein lined - continuity btwn cytoplasm and nucleus
Rough ER jobs
secreted and membrane protein biosynthesis steroid synthesis oxidative modification of xenobiotic COP II vesicle formation
Smooth ER jobs
generation of limiting membrane in autophagy
Rough and Smooth ER jobs
phospholopid and cholesterol synthesis Calcium storage (especially in muscles) MHC I ag presentation
ER client proteins
secreted proteins (enzymes, Igs, extracellular matrix proteins) integral membrane proteins of endomembrane system (receptors, transporters, channels, cell adhesion) lumenal proteins of endomembrane system (lysosomal hydrolyses, ER chaperones)
non-ER client proteins
made on free polysomes in cytoplasm and imported where they need to go cytosolic (cytosekeletal, contractile, soluble enzymes) peripheral membrane proteins on cytoplasmic face (spectrin) nuclear, mitochondrial, perixisomal proteins
translocation
protein synthesis on cytoplasmic side of ER membrane, nascent polypeptide is translocated through the protein lined channel into the lumen where modifications happen
N-linked glycosylation
HIV gp160 insulin receptor, addition of pre-assembled Glu3-man9-glcnac2 branched sugars to amide groups of Asparagine
co-translational glycosylation
the signal for glycosylation is linear! add glycosylation before polypeptide folds, enzymes transfer in ER lumen as translate - amino end of protein can be in the lumen or the cytosol, transferred over to reside
oligosaccharyl transferase
transfers phospholipid of sugars made in the ER by enzymes onto Asn of nascent polypeptide cytoplasm is a reducing environment, make it as the protein is folding, transfer from dolichol in membrane
chaperones
facilitate folding etc. in the Er
proinsulin
protein with 3 disulfide binds - needs chaperone to facilitate oxidation
BIP
chaperone binds to hydrophobic stretches of AAs in the ER i.e. proinsulin and glycoproteins bind to AAs, hydrolyze ATP, fall off, binds new stretches of hydrophobic AAs on peptide - if fold naturally, it won’t be right, BIP binds to prevent from folding in a way that can’t be unwound during/after synthesis
Calnexin-Calreticulin
chaperone i.e. HIV gp160 receptor binds to glucose! lectin properties released if protein loses glucose binds oligosaccharide with a terminal glucose to target it for degredation glucose usually trimmed when oligosccharide is added during N-linked glycosylation re-add glucose if misfolded so C-C binds
ERAD
ER associated degradation, to degrade misfolded or slowly folding proteins balance! if folds slowly –> more ERAD
ubiquitin
if protein is misfolded, retains chaperone, stays in ER translocated through membrane into cytoplasm (ATPase pulls it through) N-glycanase cleaves off glycoproteins ubiquitin ligase adds ubiquitin covalently to LYSINE (K) tags for degradation to proteasome (ubiquitin recycled)
del508 mutation
mutant CF gene poor folding and OFF (ERAD) is predominant way lacks channel so can’t regulate the ion concentration in the airways and can’t clear mucus
gain-of-function mutations
most misfolded proteins are loss-of-function some - lead to toxic accumulation of misfolded proteins, like Alzheimers, T2D –> toxic, ER stress –> trigger apoptosis
Synuclein
in fruit flies failure to fold is toxic - if overexpress, don’t fold, kill neurons if add chaperones –> mediate folding in the cytoplasm
ER stress
an imbalance btw capacity of the ER to process client proteins and load of proteins imposed on the organelle capacity: chaperones, oxidoreductases, glycosylation, protein degredation, lipids (membrane) demand: physio load, mutant proteins
ATF6, IRE1, PERK
tell when ER stress - when proteins not folding when activated –> turns on protein synthesis of what you need and inhibit what you don’t decreases load on ER but increase expression of genes that the ER needs rectifying response to ER stress
PERK
if making insulin - it’s all accumulating in the ER - not enough to make it and not enough capacity in ERAD! accumulate and cells die if no PERK - cells are destroyed! (ER response signal)
autophagy
alternate method to get rid of accumulated misfolding proteins in in ER ER–> under stress –> engulf part of cytoplasm with ER and contents –> merge with lysosome when not enough capacity and degrade by acid hydrolysis
