Calnexin
Encyclopedia
Calnexin is a 90kDa integral protein of the endoplasmic reticulum
(ER). It consists of a large (50 kDa) N-terminal calcium
-binding
lumenal
domain
, a single transmembrane helix
and a short (90 residues
), acid
ic cytoplasm
ic tail.
Calnexin is one of the chaperone molecules, which are characterized by their main function of assisting protein folding
and quality control, ensuring that only properly folded and assembled proteins proceed further along the secretory pathway
.
The function of calnexin is to retain unfolded or unassembled N-linked glycoproteins in the endoplasmic reticulum.
Calnexin binds only those N-glycoprotein
s that have GlcNAc2Man9Glc1 oligosaccharide
s.
Oligosaccharides with three sequential glucose
residues are added to asparagine
residues of the nascent proteins in the ER.
The monoglucosylated oligosaccharides that are recognized by calnexin result from the trimming of two glucose residues by the sequential action of two glucosidases, I and II. Glucosidase II can also remove the third and last glucose residue.
If the glycoprotein is not properly folded, an enzyme called UGGT
(for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin.
The improperly-folded glycoprotein chain thus loiters in the ER, risking the encounter with MNS1 (alpha-mannosidase
), which eventually sentences the underperforming glycoprotein to degradation
by removing its mannose
residue.
If the protein is correctly translated
, the chance of it being correctly folded before it encounters MNS1 is high.
ATP
and calcium ions are two of the cofactors involved in substrate binding for calnexin.
Calnexin also functions as a chaperone for the folding of MHC class I
alpha chain in the membrane of the ER. After folding is completed Calnexin is replaced by Calreticulin
, which assists in further assembly of MHC class I.
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER). It consists of a large (50 kDa) N-terminal calcium
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...
-binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
lumenal
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, a single transmembrane helix
Transmembrane helix
Transmembrane domain usually denotes a single transmembrane alpha helix of a transmembrane protein. It is called a "domain" because an alpha-helix in a membrane can fold independently from the rest of the protein, similar to domains of water-soluble proteins...
and a short (90 residues
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
), acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic tail.
Calnexin is one of the chaperone molecules, which are characterized by their main function of assisting protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
and quality control, ensuring that only properly folded and assembled proteins proceed further along the secretory pathway
Secretory pathway
The secretory pathway is a series of steps a cell uses to move proteins out of the cell; a process known as secretion. The path of a protein destined for secretion has its origins in the rough endoplasmic reticulum, a membrane-bound compartment in the cell...
.
The function of calnexin is to retain unfolded or unassembled N-linked glycoproteins in the endoplasmic reticulum.
Calnexin binds only those N-glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s that have GlcNAc2Man9Glc1 oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
s.
Oligosaccharides with three sequential glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
residues are added to asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
residues of the nascent proteins in the ER.
The monoglucosylated oligosaccharides that are recognized by calnexin result from the trimming of two glucose residues by the sequential action of two glucosidases, I and II. Glucosidase II can also remove the third and last glucose residue.
If the glycoprotein is not properly folded, an enzyme called UGGT
UGGT
UGGT, or -glucose:glycoprotein glucosyltransferase is a soluble enzyme resident in the lumen of the endoplasmic reticulum . The main function of UGGT is to recognize misfolded glycoproteins and transfer a glucose monomer to the terminal mannose on the glycoprotein...
(for UDP-glucose:glycoprotein glucosyltransferase) will add the glucose residue back onto the oligosaccharide thus regenerating the glycoprotein's ability to bind to calnexin.
The improperly-folded glycoprotein chain thus loiters in the ER, risking the encounter with MNS1 (alpha-mannosidase
Alpha-Mannosidase
alpha-Mannosidase is an enzyme involved in the cleavage of the alpha form of mannose.- Isozymes :Humans express the following three alpha-mannosidase isozymes:- Applications :...
), which eventually sentences the underperforming glycoprotein to degradation
Chemical decomposition
Chemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
by removing its mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
residue.
If the protein is correctly translated
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
, the chance of it being correctly folded before it encounters MNS1 is high.
ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
and calcium ions are two of the cofactors involved in substrate binding for calnexin.
Calnexin also functions as a chaperone for the folding of MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
alpha chain in the membrane of the ER. After folding is completed Calnexin is replaced by Calreticulin
Calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 is a protein that in humans is encoded by the CALR gene....
, which assists in further assembly of MHC class I.