KDELR

KDELR refers to the KDEL receptor family, a group of transmembrane proteins that function as cargo receptors in the early secretory pathway. They recognize soluble endoplasmic reticulum (ER) resident proteins bearing a C-terminal KDEL motif (or related variants like HDEL in some species) that have escaped to the Golgi, and mediate their retrieval back to the ER to maintain ER protein homeostasis.

Localization and structure: KDELRs are predominantly located in the Golgi apparatus and cycle between Golgi and ER membranes. In vertebrates, there are several paralogs, including KDELR1, KDELR2, and KDELR3 (and sometimes KDELR4 in certain species). They are predicted to contain multiple transmembrane helices (often described as seven) with luminal domains that bind KDEL-containing cargo and cytosolic tails that interact with retrograde transport machinery such as COPI coats.

Mechanism of action: The binding of KDEL-bearing cargo by KDELRs is favored in the acidic environment of the Golgi, promoting the assembly of COPI-coated vesicles that transport the receptor–cargo complex back to the ER. In the neutral pH of the ER lumen, the affinity decreases, releasing the cargo. The receptor recycles back to the Golgi for additional rounds of retrieval. Yeast use Erd2 as a functional homolog that recognizes HDEL, illustrating conservation of the retrieval principle across species.

Biological significance: The KDELR system is essential for retaining ER chaperones and other soluble resident proteins, ensuring proper protein folding and quality control. By maintaining ER composition, KDELRs support the efficiency of the secretory pathway and overall cellular proteostasis. Variations among KDELR paralogs can influence cargo specificity and trafficking dynamics, reflecting evolutionary adaptation in different organisms.