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#KDEL receptor

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

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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