RAGE
Encyclopedia
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for Advanced Glycation Endproducts is a 35kD transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. It is also called "AGER". Its name comes from its ability to bind advanced glycation endproducts (AGE
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
), which include chiefly glycoproteins the glycans of which have been modified non-enzymatically through the Maillard reaction
Maillard reaction
The Maillard reaction is a form of nonenzymatic browning similar to caramelization. It results from a chemical reaction between an amino acid and a reducing sugar, usually requiring heat....
. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common motif, RAGE is often referred to as a pattern recognition receptor
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...
. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1
HMGB1
High-mobility group protein B1, also known as high-mobility group protein 1 and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.HMG-1 belongs to high mobility group.-Role in Inflammation:...
). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively and by active secretion from macrophages, natural killer (NK) cells and dendritic cells.
The interaction between RAGE and its ligands is thought to result in pro-inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
activation. Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.
Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases.
Gene/polymorphisms
The human RAGE gene lies within the major histocompatibility complexMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) class III region on chromosome 6 and comprises 11 exons interlaced by 10 introns. Total length of the gene is about 1400 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s (bp) including the promoter region, which partly overlaps with the PBX2 gene. About 30 polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
are known most of which are single nucleotide polymorphisms (SNP
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
).
RNA/alternative splicing
The primary transcript of the human RAGE gene (pre-mRNA) is thought to be alternatively splicedAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
. So far about 6 isoforms including the full length transmembrane receptor have been found in different tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
such as lung, kidney, brain etc. Five of these 6 isoforms lack the transmembrane domain and are thus believed to be secreted from cells. Generally these isoforms are referred to as sRAGE (soluble RAGE) or esRAGE (endogenous secretory RAGE). One of the isoforms lacks the V-domain and is thus believed not to be able to bind RAGE ligands.
Structure
The full receptor consists of 5 domains: The cytosolic domain, which is responsible for signal transduction, the transmembrane domain which anchors the receptor in the cell membrane, the variable domain which binds the RAGE ligands and two constant domains. RAGE has a potential V domin for ligand binding. and the cytosolic domin for the cytosolic signalling.RAGE ligands
RAGE is able to bind several ligands and therefore is referred to as a pattern-recognition receptor. Ligands which have so far been found to bind RAGE are:- AGEAdvanced glycation endproductAn advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
- HMGB1HMGB1High-mobility group protein B1, also known as high-mobility group protein 1 and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.HMG-1 belongs to high mobility group.-Role in Inflammation:...
(Amphoterin) - S100b
- S100A7S100A7Protein S100-A7 also known as S100 calcium-binding protein A7 or psoriasin is a protein that in humans is encoded by the S100A7 gene.- Function :S100A7 is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs...
(psoriasin) but not highly homologous S100A15S100A15Koebnerisin also known as protein S100-A7A , S100 calcium-binding protein A7-like 1 or S100 calcium-binding protein A15 is a protein that in humans is encoded by the S100A7A gene....
(koebnerisin) - S100PS100PProtein S100-P is a protein that in humans is encoded by the S100P gene.-Interactions:S100P has been shown to interact with EZR.-Further reading:...
- Amyloid-β-protein
- Mac-1
- Phosphatidylserine.
RAGE and disease
RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesisPathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
is hypothesized to include ligand binding upon which RAGE signals activation of the nuclear factor kappa B (NF-κB). NF-κB controls several genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
which are involved in inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Interestingly, RAGE itself will also be up-regulated by NF-κB. Given a condition in which there is a large amount of RAGE ligands (e.g. AGE
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
in diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
or Amyloid-β-protein
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
in Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
) this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature in a fatal way which ends in organ damage or even organ failure. Diseases that have been linked to RAGE are:
- AtherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
- Peripheral vascular disease
- Myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
- Congestive heart failureCongestive heart failureHeart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
- Diabetic retinopathyDiabetic retinopathyDiabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
- Diabetic neuropathyDiabetic neuropathyDiabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
- Diabetic nephropathyDiabetic nephropathyDiabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
- Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
- PsoriasisPsoriasisPsoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
AGE receptors
Besides RAGE there are other receptors which are believed to bind advanced glycation endproducts. However, these receptors could play a role in removal of AGE rather than in signal transduction as it is the case for RAGE. Other AGE receptors are:- SR-A (Macrophage scavenger receptorScavenger receptorScavenger receptors are a group of receptors that recognize modified low-density lipoprotein by oxidation or acetylation. This naming is based on a function of cleaning : Scavenger receptors widely recognize and uptake macromolecules having a negative charge as well as modified LDL.-Function:It is...
Type I and II) - OST-48 (Oligosaccharyl transferase-4) (AGE-R1)
- 80 K-H phosphoprotein (Proteinkinase C substrate) (AGE-R2)
- GalectinGalectinIn molecular biology, galectins are a family of lectins which bind beta-galactoside. The family is defined by having at least one characteristic carbohydrate recognition domain with an affinity for beta-galactosides and sharing certain sequence elements...
-3 (AGE-R3) - LOX-1OLR1Oxidized low-density lipoprotein receptor 1 also known as lectin-type oxidized LDL receptor 1 is a protein that in humans is encoded by the OLR1 gene.- Function :...
(Lectin-like oxidized low density lipoprotein receptor-1) - CD-36
External links
- AGER on the Atlas of Genetics and OncologyAtlas of Genetics and Cytogenetics in Oncology and HaematologyThe Atlas of Genetics and Cytogenetics in Oncology and Haematology is a collection of resources on genes, chromosomes anomalies, leukemias, solid tumours, and cancer-prone diseases...