Practice question

Retention and retrieval of escaped ER resident proteins depends on pH-sensitive recognition of C-terminal retention signal by cycling receptor Erd2 localized predominantly in cis-Golgi and ER-Golgi intermediate compartment but trafficking constitutively. Human KDEL receptor family comprises three isoforms KDELR1-3 sharing seven-transmembrane architecture with lumenal binding pocket formed by polar residues and conserved histidine that at acidic pH around 6.2 characteristic of Golgi protonates enhancing affinity for Lys-Asp-Glu-Leu tetrapeptide and variants HDEL, RDEL. Ligand binding induces conformational change exposing cytosolic acidic motifs that recruit COPI coatomer via Arf1-GTP, ArfGAP and coatomer subunits forming retrograde vesicles returning complex to ER. Upon arrival at neutral pH around 7.2, histidine deprotonates, binding affinity drops sharply, cargo such as BiP, PDI, calreticulin dissociates to resume folding functions, receptor recycles to Golgi for another round. Receptor also signals via Gαq and Src kinase pathways regulating Golgi transport and actin dynamics. Mannose-6-phosphate tagging, lipidation, palmitoylation and N-linked glycosylation are distinct modifications targeting proteins to lysosomes, membranes or affecting stability, not retrieval of soluble lumenal chaperones bearing KDEL signal within secretory pathway and quality control.