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

5 Pages
Unlock Document

Biochemistry & Molecular Bio.
David Gross

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
More Less

Related notes for BIOCHEM 524

Log In


Join OneClass

Access over 10 million pages of study
documents for 1.3 million courses.

Sign up

Join to view


By registering, I agree to the Terms and Privacy Policies
Already have an account?
Just a few more details

So we can recommend you notes for your school.

Reset Password

Please enter below the email address you registered with and we will send you a link to reset your password.

Add your courses

Get notes from the top students in your class.