Practice question

When attempts at native conformation repeatedly fail despite chaperone assistance including BiP binding and calnexin-mediated retention plus UGGT reglucosylation cycles, terminally misfolded proteins must be removed to prevent proteotoxic aggregation, ER stress and activation of apoptotic pathways. Lumenal quality control uses mannose timer: ER mannosidase I and EDEM1-3 remove specific α1-2 mannose residues from core glycan converting Man9GlcNAc2 to Man7-6 isoforms with reduced affinity for folding lectins and increased affinity for degradation lectins. Trimmed glycans recognized by MRH domains of OS-9 and XTP3-B lectins deliver clients to membrane-embedded ubiquitin ligase complex centered on Sel1L adaptor and Hrd1 RING E3 ligase. Retrotranslocation through Derlin1-3 or Hrd1 channel itself moves polypeptide to cytosol where E2 conjugases Ubc6 and Ubc7 add K48-linked polyubiquitin chains, AAA ATPase p97/VCP with cofactors Ufd1-Npl4 provides mechanical pulling force extracting substrate, and 26S proteasome degrades it. Non-glycosylated misfolded proteins recognized via BiP and similar ERAD adaptors and ubiquitin ligase Doa10, maintaining proteome integrity and freeing chaperone capacity for new synthesis and folding attempts and organismal homeostasis.