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

• Administration of aFGF-PE40 or aFGF-PE4E KDEL with heparin inhibits the growth of established KB and preestablished A431 epidermoid carcinoma xenografts in athymic mice [11].
• A novel glycoprotein of feline infectious peritonitis coronavirus contains a KDEL-like endoplasmic reticulum retention signal [12].

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].

References