Calreticulin
Encyclopedia
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
.
Calreticulin is a multifunctional protein
that binds Ca2+
ion
s (a second messenger in signal transduction
), rendering it inactive. The Ca2+ is bound with low affinity
, but high capacity
, and can be released on a signal (see inositol triphosphate
). Calreticulin is located in storage compartments associated with the endoplasmic reticulum
.
The term "Mobilferrin" is considered to be the same as calreticulin by some sources.
to the Golgi apparatus
.
A similar quality-control chaperone, calnexin
, performs the same service for soluble proteins as does calreticulin. Both proteins, Calnexin and calreticulin, have the function of binding to oligosaccharide
s containing terminal glucose residues, thereby targeting them for degradation. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation
is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the RER will re-add glucose residues so that other Calreticulin/Calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.
Studies on transgenic mice reveal that calreticulin is cardiac embryonic gene that is essential during development.
of the superfamily of nuclear receptor
s. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor
and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor
to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor
transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
in certain sera of systemic lupus
and Sjogren
patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM
classes.
s to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed, is the presence of another molecule with signal CD47
, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia
and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.
with Perforin
and NK2 homeobox 1.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CALR 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...
.
Calreticulin is a multifunctional protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that binds Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s (a second messenger in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
), rendering it inactive. The Ca2+ is bound with low affinity
Chemical affinity
In chemical physics and physical chemistry, chemical affinity is the electronic property by which dissimilar chemical species are capable of forming chemical compounds...
, but high capacity
Valence (chemistry)
In chemistry, valence, also known as valency or valence number, is a measure of the number of bonds formed by an atom of a given element. "Valence" can be defined as the number of valence bonds...
, and can be released on a signal (see inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
). Calreticulin is located in storage compartments associated with the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
.
The term "Mobilferrin" is considered to be the same as calreticulin by some sources.
Function
Calreticulin binds to misfolded proteins and prevents them from being exported from the Endoplasmic reticulumEndoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
to the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
.
A similar quality-control chaperone, calnexin
Calnexin
Calnexin is a 90kDa integral protein of the endoplasmic reticulum . It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short , acidic cytoplasmic tail....
, performs the same service for soluble proteins as does calreticulin. Both proteins, Calnexin and calreticulin, have the function of binding to oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
s containing terminal glucose residues, thereby targeting them for degradation. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the RER will re-add glucose residues so that other Calreticulin/Calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.
Studies on transgenic mice reveal that calreticulin is cardiac embryonic gene that is essential during development.
Transcription regulation
Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domainDNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
of the superfamily of nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
s. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
Clinical significance
Calreticulin binds to antibodiesAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
in certain sera of systemic lupus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
and Sjogren
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....
patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
classes.
Role in cancer
Calreticulin (CRT) is expressed in many cancer cells and plays a role to promote macrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed, is the presence of another molecule with signal CD47
CD47
CD47 is a protein that in humans is encoded by the CD47 gene.- Function :CD47 is a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix...
, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia
Myeloid leukemia
Myeloid leukemia is a type of leukemia affecting myeloid tissue.Types include:* Acute myeloid leukemia* Chronic myelogenous leukemia...
and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.
Interactions
Calreticulin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Perforin
Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
and NK2 homeobox 1.