Membrane Trafficking, ER & Protein Folding, ERAD, UPR & Major Pathways

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Department
Biochemistry & Molecular Bio.
Course
BIOCHEM 524
Professor
David Gross
Semester
Fall

Description
March 28 • The majority of luminal & secreted proteins contain N-linked glycans o glycosylation occurs co-translocationally via the integral membrane oligosaccharyl transferase and dolichol phosphate donor o the glycan on cell surface proteins act as protective coating for the cell • Membrane trafficking o distribution & localization of all luminal & endomembrane system o proteins (cargo) are packaged into vesicles & moved from donor to target membrane compartments o cargo is delivered by membrane budding & fusion o this is bulk transport, many different proteins delivered while already folded • Protein folding in ER lumen o facilitated by molecular chaperones, recognize unfolded polypeps & their N- linked oligosaccharide units (glycans)  calnexin & calreticulin contain chaperone & lectin domains  glycan marking & trimming are used to monitor the folding state of the polypep. • trimming by glucosidases in ER lumen generate glycan that’s recognized by calnexin or calreticulin lectin chaperones which retains protein in ER while undergoing folding  after being released from lectins, glucosidase trims another glucose from the glycan, if protein folded properly it exits the ER, if not a glucosyl transferase adds back a glucose and the cycle repeats • glucosyl transferase both enzyme & chaperone, keeps incompletely folded protein from aggregating & adds glucose markers to trigger reentry to cycle • 3 Fates of newly synthesized proteins in ER lumen o properly fold & exit ER o misfold & are removed from ER by ER associated protein degradation (ERAD) o misfold & aggregate in ER (leads to disease) • ERAD o essentially reverse of protein translocation  retrotranslocation  N-linked oligosaccharide hydrolysis  ubiquitinylation  proteolysis  as many as 35% of new proteins degraded via this quality control mech. o process:  chaperone connects to miss folded protein, brings it to ER lumen membrane  a protein translocator w/ accessory proteins translocates miss folded protein into cytosol  chaperone in cytosol connects  N-glycanase polyubiquitinylates miss folded protein  proteasome recognizes polyubiquitinylate tag, degrades miss folded protein • Protein misfolding & aggregation o toxic for the cell o elaborate quality control mech’s have evolved (known as unfolded protein response (UPR)) o unfolded proteins can occur because:  temperature stress  expression of proteins w/ mutations that result in misfolding  redox stress • Cystic fibrosis o well studied example of protein misfolding disease o cause:  CFTR channel moves chloride ions to outside of cell, mutant CFTR channel doesn’t, causes mucus to build up on outside of cell  caused by deletion of Phe in the normal CFTR sequence
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