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#ER retention

2 public questions tagged with this topic.

Protein Sorting and Trafficking

The ER retention signal KDEL is recognized by:

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.

Ref: Munro & Pelham, Cell 48: 1987, KDEL Receptor Erd2 Recognizing KDEL Signal.

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Protein Sorting and Trafficking

Proteins with the KDEL signal are retrieved from:

Lumenal residents of endoplasmic reticulum that perform folding, such as BiP/GRP78, protein disulfide isomerase, calreticulin and Grp94, must be retained despite continuous bulk flow to Golgi. Retention is achieved by C-terminal tetrapeptide KDEL or variants HDEL in yeast for soluble proteins and Lys-Lys-X-X or Arg-X-Arg motifs for type I membrane proteins. Escaped proteins reach cis-Golgi and ER-Golgi intermediate compartment where seven-transmembrane KDEL receptor Erd2, actually three isoforms KDELR1-3 in mammals, cycles constitutively between ER and Golgi. At mildly acidic Golgi pH near 6.2, histidine in lumenal binding pocket protonated enhancing affinity for KDEL peptide, stabilizing active receptor conformation whose cytosolic tail recruits COPI coatomer via Arf1-GTP and ArfGAP. Retrograde vesicles return receptor-cargo to ER where neutral pH near 7.2 reduces binding, cargo releases to resume folding functions, and receptor recycles for reuse. This retrieval loop, not degradation, maintains high local concentration of folding machinery, prevents inappropriate secretion and provides quality control opportunity to assist maturation of client proteins before ER exit and forward transport. Additional coordination with cellular stress pathways ensures fidelity, prevents aggregation, and links trafficking to growth control and proteostasis maintenance across diverse cell types and developmental stages.

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Chapter 12: KDEL Retrieval via Erd2 and COPI Vesicles.

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