Alternative titles; symbols
HGNC Approved Gene Symbol: KDELR1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,382,575-48,397,412 (from NCBI)
Resident soluble proteins within the lumen of the endoplasmic reticulum (ER) are retained there by virtue of a C-terminal tetrapeptide ER retention signal, commonly lys-asp-glu-leu (KDEL) in mammals. KDELR1 cycles between the Golgi apparatus and the ER, returning proteins containing the KDEL signal to the ER (Lewis and Pelham, 1992).
By PCR of a T-cell cDNA library using degenerate primers based on yeast ERD2, followed by screening a placenta cDNA library, Lewis and Pelham (1990) cloned KDELR1. The deduced 212-amino acid protein has 7 hydrophobic regions and shares 50% identity with the yeast receptor. Following expression in COS cells, epitope tagged KDELR1 concentrated in the Golgi apparatus and in punctate structures that may have been transport vesicles or functional intermediates between the ER and Golgi.
Lewis and Pelham (1992) found that overexpression of human ERD2 improved the retention of a protein with a weakly recognized variant of the KDEL retention signal, DDEL. Overexpression of KDEL or DDEL ligands caused redistribution of ERD2 from the Golgi apparatus to the ER, and mutation of ERD2 altered the ligand specificity of this redistribution. The authors concluded that ligand control of receptor movement may limit retrograde flow and minimize fruitless recycling of secretory proteins.
Hsu et al. (1992) found that about half of KDELR1- or KDELR2 (609024)-transfected COS cells expressed the receptors in a juxtanuclear, Golgi-like pattern, while the remainder showed a reticular, ER-like pattern with nuclear envelope staining. Overexpression of the KDEL receptors led to the ER-like pattern and was associated with the collapse of the Golgi apparatus into the ER, as seen in cells treated with brefeldin A. In addition to the loss of the Golgi apparatus as a distinct organelle, overexpression resulted in redistribution of the Golgi coat protein, beta-COP (COPB; 600959), to the cytosol, addition of complex oligosaccharides to resident ER glycoproteins, and blockage of anterograde traffic. Hsu et al. (1992) concluded that the KDEL receptors provide signals that regulate retrograde traffic between the Golgi and the ER.
Townsley et al. (1993) expressed mutant forms of KDELR1 in COS cells and examined their intracellular locations and ligand-binding capacities. They found that ligand binding was dependent on charged residues within the transmembrane domains. Retrograde transport of occupied receptors was unaffected by most mutations in the cytoplasmic loops, but was critically dependent upon asp193 in transmembrane domain 7. Retention in the Golgi apparatus required neither ligand binding nor asp193. Townsley et al. (1993) concluded that movement of the receptor is controlled by conformational changes and intermolecular interactions within the membrane bilayer.
By genomic sequence analysis, Smith et al. (2000) mapped the KDELR1 gene to chromosome 19q13.3.
Hamada et al. (2004) created transgenic mice expressing a transport-defective human KDEL receptor. The mutant receptor sensitized cells to ER stress, and mutant mice developed dilated cardiomyopathy. Ultrastructural analysis revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of mutant cardiomyocytes. Mutant cardiomyocytes were sensitive to ER stress following treatment with an N-glycosylation inhibitor, and they showed a functional defect in the L-type Ca(2+) current. The authors observed ubiquitinated protein aggregates, enhanced expression of Chop (126337), a death-related transcriptional factor expressed upon ER stress, and apoptosis in the mutant hearts. Hamada et al. (2004) concluded that impairment of the KDEL receptor disturbed ER quality control, resulting in accumulation of misfolded proteins in the ER, and that the dilated cardiomyopathy in transgenic mice was associated with ER stress.
Hamada, H., Suzuki, M., Yuasa, S., Mimura, N., Shinozuka, N., Takada, Y., Suzuki, M., Nishino, T., Nakaya, H., Koseki, H., Aoe, T. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Molec. Cell. Biol. 24: 8007-8017, 2004. [PubMed: 15340063] [Full Text: https://doi.org/10.1128/MCB.24.18.8007-8017.2004]
Hsu, V. W., Shah, N., Klausner, R. D. A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1. Cell 69: 625-635, 1992. [PubMed: 1316805] [Full Text: https://doi.org/10.1016/0092-8674(92)90226-3]
Lewis, M. J., Pelham, H. R. B. A human homologue of the yeast HDEL receptor. Nature 348: 162-163, 1990. [PubMed: 2172835] [Full Text: https://doi.org/10.1038/348162a0]
Lewis, M. J., Pelham, H. R. B. Ligand-induced redistribution of a human KDEL receptor from the Golgi complex to the endoplasmic reticulum. Cell 68: 353-364, 1992. [PubMed: 1310258] [Full Text: https://doi.org/10.1016/0092-8674(92)90476-s]
Smith, J. S., Tachibana, I., Pohl, U., Lee, H. K., Thanarajasingam, U., Portier, B. P., Ueki, K., Ramaswamy, S., Billings, S. J., Mohrenweiser, H. W., Louis, D. N., Jenkins, R. B. A transcript map of the chromosome 19q-arm glioma tumor suppressor region. Genomics 64: 44-50, 2000. [PubMed: 10708517] [Full Text: https://doi.org/10.1006/geno.1999.6101]
Townsley, F. M., Wilson, D. W., Pelham, H. R. B. Mutational analysis of the human KDEL receptor: distinct structural requirements for Golgi retention, ligand binding and retrograde transport. EMBO J. 12: 2821-2829, 1993. [PubMed: 8392934] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05943.x]