KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1, also known as KDELR1, is a protein which in humans is encoded by the KDELR1 gene. [1] [2]
Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continual retrieval from the cis-Golgi or a pre-Golgi compartment. Sorting of these proteins is dependent on a C-terminal tetrapeptide signal, usually lys-asp-glu-leu (KDEL) in animal cells and his-asp-glu-leu (HDEL) in S. cerevisiae . This process is mediated by a receptor that recognizes and binds the tetrapeptide-containing protein and then returns it to the ER. In yeast, the sorting receptor is encoded by a single gene, ERD2, which is a seven-transmembrane protein. Unlike yeast, several human homologs of the ERD2 gene, constituting the KDEL receptor gene family, have been described. The protein encoded by this gene was the first member of the family to be identified, and it encodes a protein structurally and functionally similar to the yeast ERD2 gene product. [2] The KDEL receptor mediates the retrieval of misfolded proteins between the ER and the Golgi apparatus. [7] The KDEL receptor functions by binding to endoplasmic reticulum chaperones. [7] These chaperones are recognized by the KDEL receptor in downstream compartments of the ER. Once bound, they are packaged into coat protein complex I vesicles for retrograde transport to the ER. [8] In vitro studies in yeast have revealed that this receptor regulates membrane transport in the early stages of the secretory pathway from ER to the Golgi. [8] An error or mutation in the KDEL receptor disturbs the ER quality control and diseases associated with ER stress are observed. [9]
KDEL receptors have been implicated in the development of dilated cardiomyopathy (DCM). To determine the relationship between KDEL receptor and dilated cardiomyopathy, transgenic mice with a point mutation (D193N) were made. [7] The mice expressing the transport mutant D193N gene grew normally until they reached adulthood. The mutant KDEL receptor did not function after 14 weeks of age, and these mice developed DCM. They were observed to have dilated heart chambers, as well as higher heart-to-body ratios with enlarged hearts, and the cardiac myocytes were larger in size. [7] No difference was observed in arterial blood pressure between wild-type and mutant mice, thus cardiomegaly was not attributed to hypertension. [7] Upon analysis, it was found that KDEL mutant mice had proliferation in their sarcoplasmic reticulum (SR) and a narrowing in the transverse tubule compared to the wild-type and controls. Moreover, aggregations of degenerative membrane proteins were observed in the expanded SR. This suggests that the mutant KDEL receptor leads to impaired recycling and quality control of the ER, which leads to aggregation of misfolded proteins in the ER. Furthermore, KDEL D193N transgenic mice had defects in the L-type Ca++ channel current in ventricular myocytes. [7] The basal current of these channels was significantly lower than the controls. L-type channels expression was lower in the plasma membrane of the KDEL D193N heart cells due to the narrowing of transverse tubules. [7] BiP, a chaperone protein, was unevenly distributed and synthesized in larger proportion in the transgenic mutant mice, which suggests that there was an increase in concentration of misfolded proteins. [7] They also observed aggregates of the ubiquitin-proteasome system (a degradation system); this suggests that there was saturation of the system due to the high levels of misfolded proteins that lead to impaired ER quality control. [7] The researchers concluded that hyperubiquitination and saturation of the proteasome system results due to the accumulation of misfolded protein, which induces stress. [7] The accumulation of misfolded proteins induced by ER stress has also been observed in human DCM. [10] A murine DCM study found an increase in apoptosis due to the high levels of CHOP expression. CHOP is a transcription factor that is elevated during ER stress and causes apoptosis of cells during the process of an unfolded protein response. [11] Increase pressure load/mechanical stress in KDEL D193N mice caused an even greater synthesis of BiP, CHOP and other proteins that are biomarkers of cellular stress and ER stress as the capacity of the ER to deal with this is very limited. [7]
KDELR1 is also critical for the development of lymphocytes. Mice with a Y158C missense mutation in Kdelr1 have reduced numbers of B and T lymphocytes, and a more susceptible to viral infection. [12]
The structure of Gallus gallus KDELR2 (Uniprot Q5ZKX9) has been solved in the Apo state, KDEL peptide-bound state, and bound to a synthetic nanobody. [15] Sequence identity between human KDELR1 and chicken KDELR2 is 84.4%.
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene.
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.
COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.
ER retention refers to proteins that are retained in the endoplasmic reticulum, or ER, after folding; these are known as ER resident proteins.
Calnexin (CNX) is a 67kDa integral protein of the endoplasmic reticulum (ER). It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short, acidic cytoplasmic tail.
Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms.
Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.
Binding immunoglobulin protein (BiP) also known as (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) or (Byun1) is a protein that in humans is encoded by the HSPA5 gene.
ADP-ribosylation factor GTPase-activating protein 1 is an enzyme that in humans is encoded by the ARFGAP1 gene. Two transcript variants encoding different isoforms have been found for this gene.
Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1 gene. Derlin-1 is located in the membrane of the endoplasmic reticulum (ER) and is involved in retrotranslocation of specific misfolded proteins and in ER stress. Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues. The protein belongs to the Derlin-family proteins consisting of derlin-1, derlin-2 and derlin-3 that are components in the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER, and are named ‘der’ for their ‘Degradation in the ER’. Derlin-1 is a mammalian homologue of the yeast DER1 protein, a protein involved in the yeast ERAD pathway. Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins.
Sec23 homolog A , also known as SEC23A, is a protein which in humans is encoded by the SEC23A gene.
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.
BET1 homolog is a protein that in humans is encoded by the BET1 gene.
ER lumen protein retaining receptor 2 is a protein that in humans is encoded by the KDELR2 gene.
ER lumen protein retaining receptor 3 is a protein that in humans is encoded by the KDELR3 gene.
Reticulons are a group of evolutionary conservative proteins residing predominantly in endoplasmic reticulum, primarily playing a role in promoting membrane curvature. In addition, reticulons may play a role in nuclear pore complex formation, vesicle formation, and other processes yet to be defined. They have also been linked to oligodendrocyte roles in inhibition of neurite outgrowth. Some studies link RTNs with Alzheimer's disease and amyotrophic lateral sclerosis.
KDEL is a target peptide sequence in mammals and plants located on the C-terminal end of the amino acid structure of a protein. The KDEL sequence prevents a protein from being secreted from the endoplasmic reticulum (ER) and facilitates its return if it is accidentally exported.
KKXX and for some proteins XKXX is a target peptide motif located in the C terminus in the amino acid structure of a protein responsible for retrieval of endoplasmic reticulum (ER) membrane proteins to and from the Golgi apparatus. These ER membrane proteins are transmembrane proteins that are then embedded into the ER membrane after transport from the Golgi. This motif is exclusively cytoplasmic and interacts with the COPI protein complex to target the ER from the cis end of the Golgi apparatus by retrograde transport.
HDEL is a target peptide sequence in plants and yeasts located on the C-terminal end of the amino acid structure of a protein. The HDEL sequence prevents a protein from being secreted from the endoplasmic reticulum (ER) and facilitates its return if it is accidentally exported.
