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#protein retrieval

2 public questions tagged with this topic.

Protein Sorting and Trafficking

How does the KDEL receptor regulate protein retrieval?

ER lumen contains chaperones BiP HSPA5, Grp94 HSP90B1, PDI family, calreticulin that may leak into Golgi during non-selective bulk flow; retention therefore relies on active retrieval not static retention. Soluble residents carry C-terminal KDEL tetrapeptide Lys-Asp-Glu-Leu or variant HDEL. If they escape to cis-Golgi beyond, KDEL receptors family of seven-transmembrane proteins Erd2 in yeast KDELR1-3 in mammals concentrated in Golgi and ERGIC recognize tetrapeptide. Binding strongly pH dependent because histidine residues protonate at mildly acidic Golgi lumen pH 6.0-6.2 stabilizing interaction with C-terminus, while neutral ER lumen pH 7.2-7.4 causes proton release dramatic loss affinity causing dissociation. Ligand-bound receptors packaged into COPI vesicles for retrograde return via dilysine-like signals on receptor tails binding coatomer. Upon reaching ER cargo dissociates spontaneously without covalent modification. Free receptors recycle forward via COPII. pH sensor mechanism ensures unidirectional net return without phosphorylation or SNARE inhibition, explaining why neutralization of Golgi pH causes ER protein secretion.

Ref: Alberts et al., MBC Chapter 13: KDEL receptor pH-dependent retrieval to ER via COPI.

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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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