Practice question

ER-associated degradation provides clearance mechanism for terminally misfolded or orphan unassembled subunits that cannot be rescued by chaperones. Commitment step involves N-glycan mannose trimming as timer: ER mannosidase I and EDEM1-3, homologous to yeast Htm1, remove specific α1-2 mannose residues from high-mannose precursor Man9GlcNAc2 generating Man7-Man5 species exposing α1-6 mannose recognized as degradation signal. Trimmed glycans bound by MRH domains of degradation lectins OS-9 and XTP3-B that deliver clients to membrane-integrated ubiquitination apparatus comprising scaffold Sel1L and RING-type E3 ligases Hrd1 for lumenal lesions and Doa10 for membrane lesions. Retrotranslocation debated whether via Derlin1-3 rhomboid pseudoproteases, Sec61 channel or Hrd1 itself as conduit moves protein to cytosol where conjugating enzymes Ubc6 and Ubc7 polyubiquitinate lysine residues with K11 and K48 linkages. AAA ATPase p97/VCP hexamer with cofactors Ufd1 and Npl4 provides mechanical pulling. Shuttle factors Rad23 and Dsk2 deliver ubiquitinated substrates to 26S proteasome for degradation. Glucosyltransferase, PDI or Sec63 participate in folding attempts rather than degradation commitment, while mannosidase trimming irreversibly marks proteins for disposal ensuring fidelity of secretory pathway and preventing toxic accumulation and ER stress.