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Gene Review

KDELC1  -  KDEL (Lys-Asp-Glu-Leu) containing 1

Homo sapiens

Synonyms: EP58, ER protein 58, ERp58, Endoplasmic reticulum resident protein 58, KDEL motif-containing protein 1, ...
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Disease relevance of KDELC1

  • Targeting of cholera toxin and Escherichia coli heat labile toxin in polarized epithelia: role of COOH-terminal KDEL [1].
  • An alfalfa mosaic virus untranslated leader sequence and Lys-Asp-Glu-Leu (KDEL) endoplasmic reticulum retention signal were linked at the N and C terminus of the heavy chain, respectively. mAbP was as effective at neutralizing the activity of the rabies virus as the mammalian-derived antibody (mAbM) or human rabies Ig (HRIG) [2].
  • We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PEdelta53L/TGF-alpha/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing [3].
  • To investigate the possible role and mechanism of this lysosomal protease in metastasis, we transfected low-metastatic rat tumor cells with wild-type human cathepsin D, or mutated forms obtained by insertion of a KDEL peptide signal responsible for ER retention, or a control KDAS peptide [4].
  • Recombinant immunotoxins (rITs) were made from 3 ELISA-positive scFv phages by fusion to a 38 kDa truncated mutant of Pseudomonas exotoxin (PE38) with or without a KDEL mutant sequence at the C terminus [5].

High impact information on KDELC1

  • Resident luminal endoplasmic reticulum (ER) proteins carry a targeting signal (usually KDEL in animal cells) that allows their retrieval from later stages of the secretory pathway [6].
  • Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually Lys-Asp-Glu-Leu (KDEL in the single letter code) in animal cells, His-Asp-Glu-Leu (HDEL) in Saccharomyces cerevisiae [7].
  • Retention of these resident proteins in the ER is dependent on a carboxy-terminal signal, which in animal cells is usually Lys-Asp-Glu-Leu (KDEL) [8].
  • Many proteins retained within the endo/sarcoplasmic reticulum (ER/SR) lumen express the COOH-terminal tetrapeptide KDEL, by which they continuously recycle from the Golgi complex; however, others do not express the KDEL retrieval signal [9].
  • This nucleoside diphosphatase is a ubiquitously expressed, soluble 45 kDa glycoprotein devoid of transmembrane domains and KDEL-related ER localization sequences [10].

Chemical compound and disease context of KDELC1


Biological context of KDELC1

  • By searching a mouse EST database for records containing the nucleotide sequence encoding the KDEL motif, we extracted cDNAs encoding putative novel ER-resident proteins in addition to all of the known ER proteins bearing the KDEL motif [13].
  • A N-glycosylation site can be deduced and a C-terminal KDEL amino acid sequence is detected [14].
  • Biochemical support for this unusual origin now comes from the composition of the purified organelle, which contains large amounts of a 45-kDa cysteine endoprotease precursor with a C-terminal KDEL motif and the endoplasmic reticulum lumen residents BiP (binding protein) and protein disulfide isomerase [15].
  • The role of the ErbB family in supporting the malignant phenotype was characterized by stable transfection of a single chain antibody (ScFv5R) against ErbB2 containing a KDEL endoplasmic reticulum retention sequence into GEO human colon carcinoma cells [16].
  • The core protein not only has motifs permitting glycosylation as a proteoglycan, but also possesses the endoplasmic reticulum retrieval signal, KDEL, which suggests that, in addition to its role as a basement membrane component, it may also participate in the secretory pathway of cells [17].

Anatomical context of KDELC1

  • Several endoplasmic reticulum (ER)-resident proteins contain a unique C-terminal sequence (KDEL) which is required for the retention of these proteins in the ER [13].
  • When these KDEL proteins leave the ER to reach the Golgi complex, they are recognized by their receptor and transported retrograde in COPI-coated vesicles back to the ER [18].
  • Altered cDNAs encoding pro-NPY with KDEL, DKEL, RDEL, KNEL, KDQL, or KDEA at the COOH terminus were used to generate stable AtT-20 cell lines [19].
  • With time, the KDEL-containing CD8 form reaches the trans/trans-Golgi network compartments, where the protein is terminally glycosylated [20].
  • In immunofluorescence experiments, LH co-localizes with a KDEL-containing protein, protein disulfide isomerase (PDI), and also co-sediments with it after fractionation of subcellular organelles by sucrose density gradient centrifugation [21].

Associations of KDELC1 with chemical compounds

  • Similarity of the EP58 sequence with bacterial and fungus proteins suggests a possible role for EP58 in polysaccharide biosynthesis [13].
  • Acidification of isolated ricinosomes causes castor bean cysteine endopeptidase activation, with cleavage of the N-terminal propeptide and the C-terminal KDEL motif [15].
  • Cells expressing CTLA4-KDEL do not up-regulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-immunoglobin (Ig) [22].
  • It is a homodimer and does not contain either of the two previously characterized ER-specific retention motifs (KDEL or the double lysine motif) in its primary structure [21].
  • The CSDL tetrapeptide carries the free cysteine (Cys-580) involved in subunit assembly, yet it fails to function as a KDEL-type retention signal [23].

Other interactions of KDELC1

  • KDELC1 has a predicted filamin domain and BIVM contains an immunoglobulin-like motif [24].

Analytical, diagnostic and therapeutic context of KDELC1

  • Western blot analysis, peptide sequencing, and mass spectrometry demonstrate retention of KDEL in the protease proform [15].
  • To further investigate the nature of the KDEL retention signal, oligonucleotide-directed mutagenesis and transfection was used to generate stable mouse anterior pituitary AtT-20 cell lines expressing pro-NPY mutants with variants of the KDEL sequence added to their direct carboxyl terminus [25].
  • Through fusion of MHBs to the ER-retention signal KDEL, it was shown that the intracellular retention does not generate the transcriptional activator function [26].
  • Immunoprecipitation experiments show that hMCHR1-T255A has reduced glycosylation compared with the wild-type receptor and is associated with the chaperone protein, calnexin, and it colocalizes in the endoplasmic reticulum with KDEL-containing proteins [27].
  • These results indicate that plant genetic engineering could provide an effective and inexpensive means to control the glycosylation of therapeutic proteins such as mAbs, by the addition of a KDEL signal as a regulatory element [28].


  1. Targeting of cholera toxin and Escherichia coli heat labile toxin in polarized epithelia: role of COOH-terminal KDEL. Lencer, W.I., Constable, C., Moe, S., Jobling, M.G., Webb, H.M., Ruston, S., Madara, J.L., Hirst, T.R., Holmes, R.K. J. Cell Biol. (1995) [Pubmed]
  2. Function and glycosylation of plant-derived antiviral monoclonal antibody. Ko, K., Tekoah, Y., Rudd, P.M., Harvey, D.J., Dwek, R.A., Spitsin, S., Hanlon, C.A., Rupprecht, C., Dietzschold, B., Golovkin, M., Koprowski, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. Modulation of apoptotic response of a radiation-resistant human carcinoma by Pseudomonas exotoxin-chimeric protein. Seetharam, S., Nodzenski, E., Beckett, M.A., Heimann, R., Cha, A., Margulies, I., Pastan, I., Kufe, D.W., Weichselbaum, R.R. Cancer Res. (1998) [Pubmed]
  4. Cathepsin D maturation and its stimulatory effect on metastasis are prevented by addition of KDEL retention signal. Liaudet, E., Garcia, M., Rochefort, H. Oncogene (1994) [Pubmed]
  5. Isolation of new anti-CD30 scFvs from DNA-immunized mice by phage display and biologic activity of recombinant immunotoxins produced by fusion with truncated pseudomonas exotoxin. Rozemuller, H., Chowdhury, P.S., Pastan, I., Kreitman, R.J. Int. J. Cancer (2001) [Pubmed]
  6. Ligand-induced redistribution of a human KDEL receptor from the Golgi complex to the endoplasmic reticulum. Lewis, M.J., Pelham, H.R. Cell (1992) [Pubmed]
  7. A human homologue of the yeast HDEL receptor. Lewis, M.J., Pelham, H.R. Nature (1990) [Pubmed]
  8. The retention signal for soluble proteins of the endoplasmic reticulum. Pelham, H.R. Trends Biochem. Sci. (1990) [Pubmed]
  9. Head-to-tail oligomerization of calsequestrin: a novel mechanism for heterogeneous distribution of endoplasmic reticulum luminal proteins. Gatti, G., Trifari, S., Mesaeli, N., Parker, J.M., Michalak, M., Meldolesi, J. J. Cell Biol. (2001) [Pubmed]
  10. Glycoprotein reglucosylation and nucleotide sugar utilization in the secretory pathway: identification of a nucleoside diphosphatase in the endoplasmic reticulum. Trombetta, E.S., Helenius, A. EMBO J. (1999) [Pubmed]
  11. In vivo activities of acidic fibroblast growth factor-Pseudomonas exotoxin fusion proteins. Siegall, C.B., Gawlak, S.L., Chace, D.F., Merwin, J.R., Pastan, I. Bioconjug. Chem. (1994) [Pubmed]
  12. A novel glycoprotein of feline infectious peritonitis coronavirus contains a KDEL-like endoplasmic reticulum retention signal. Vennema, H., Heijnen, L., Rottier, P.J., Horzinek, M.C., Spaan, W.J. Adv. Exp. Med. Biol. (1993) [Pubmed]
  13. Identification of a novel mammalian endoplasmic reticulum-resident KDEL protein using an EST database motif search. Kimata, Y., Ooboki, K., Nomura-Furuwatari, C., Hosoda, A., Tsuru, A., Kohno, K. Gene (2000) [Pubmed]
  14. cDNA clones of the auxin-binding protein from corn coleoptiles (Zea mays L.): isolation and characterization by immunological methods. Tillmann, U., Viola, G., Kayser, B., Siemeister, G., Hesse, T., Palme, K., Löbler, M., Klämbt, D. EMBO J. (1989) [Pubmed]
  15. The ricinosomes of senescing plant tissue bud from the endoplasmic reticulum. Schmid, M., Simpson, D.J., Sarioglu, H., Lottspeich, F., Gietl, C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  16. Reorganization of ErbB family and cell survival signaling after Knock-down of ErbB2 in colon cancer cells. Hu, Y.P., Venkateswarlu, S., Sergina, N., Howell, G., St Clair, P., Humphrey, L.E., Li, W., Hauser, J., Zborowska, E., Willson, J.K., Brattain, M.G. J. Biol. Chem. (2005) [Pubmed]
  17. Molecular characterization of a novel basement membrane-associated proteoglycan, leprecan. Wassenhove-McCarthy, D.J., McCarthy, K.J. J. Biol. Chem. (1999) [Pubmed]
  18. Modulation of intracellular transport by transported proteins: insight from regulation of COPI-mediated transport. Aoe, T., Lee, A.J., van Donselaar, E., Peters, P.J., Hsu, V.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  19. Variants of the carboxyl-terminal KDEL sequence direct intracellular retention. Andres, D.A., Dickerson, I.M., Dixon, J.E. J. Biol. Chem. (1990) [Pubmed]
  20. Different fate of a single reporter protein containing KDEL or KKXX targeting signals stably expressed in mammalian cells. Martire, G., Mottola, G., Pascale, M.C., Malagolini, N., Turrini, I., Serafini-Cessi, F., Jackson, M.R., Bonatti, S. J. Biol. Chem. (1996) [Pubmed]
  21. Lysyl hydroxylase, a collagen processing enzyme, exemplifies a novel class of luminally-oriented peripheral membrane proteins in the endoplasmic reticulum. Kellokumpu, S., Sormunen, R., Heikkinen, J., Myllylä, R. J. Biol. Chem. (1994) [Pubmed]
  22. Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression. Tan, P.H., Yates, J.B., Xue, S.A., Chan, C., Jordan, W.J., Harper, J.E., Watson, M.P., Dong, R., Ritter, M.A., Lechler, R.I., Lombardi, G., George, A.J. Blood (2005) [Pubmed]
  23. Reversal of signal-mediated cellular retention by subunit assembly of human acetylcholinesterase. Velan, B., Kronman, C., Flashner, Y., Shafferman, A. J. Biol. Chem. (1994) [Pubmed]
  24. Linkage disequilibrium analysis in the LOC93081-KDELC1-BIVM region on 13q in bipolar disorder. Ferraren, D.O., Liu, C., Badner, J.A., Corona, W., Rezvani, A., Monje, V.D., Gershon, E.S., Bonner, T.I., Detera-Wadleigh, S.D. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  25. Characterization of the carboxyl-terminal sequences responsible for protein retention in the endoplasmic reticulum. Andres, D.A., Rhodes, J.D., Meisel, R.L., Dixon, J.E. J. Biol. Chem. (1991) [Pubmed]
  26. Characterization of essential domains for the functionality of the MHBst transcriptional activator and identification of a minimal MHBst activator. Hildt, E., Urban, S., Hofschneider, P.H. Oncogene (1995) [Pubmed]
  27. A point mutation in the human melanin concentrating hormone receptor 1 reveals an important domain for cellular trafficking. Fan, J., Perry, S.J., Gao, Y., Schwarz, D.A., Maki, R.A. Mol. Endocrinol. (2005) [Pubmed]
  28. Controlled glycosylation of therapeutic antibodies in plants. Tekoah, Y., Ko, K., Koprowski, H., Harvey, D.J., Wormald, M.R., Dwek, R.A., Rudd, P.M. Arch. Biochem. Biophys. (2004) [Pubmed]
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