Calnexin (CNX) is
67kDaintegral protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane protein, ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. ...
(that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the
endoplasmic reticulum
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 ( ...
(ER). It consists of a large (50 kDa)
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
-
binding lumenal domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
, a single
transmembrane helix
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...
and a short (90
residues),
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
ic
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic tail.
Function
Calnexin is a
chaperone, characterized by assisting
protein folding
Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...
and quality control, ensuring that only properly folded and assembled proteins proceed further along the
secretory pathway 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...
. It specifically acts to retain unfolded or unassembled N-linked
glycoproteins
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
in the ER.
Calnexin binds only those N-
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s that have GlcNAc2Man9Glc1
oligosaccharide
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
s.
These monoglucosylated oligosaccharides result from the trimming of two glucose residues by the sequential action of two
glucosidase
Glucosidases are the glycoside hydrolase enzymes categorized under the EC number 3.2.1.
Function
Alpha-glucosidases are enzymes involved in breaking down complex carbohydrates such as starch and glycogen into their monomers.
They catalyze t ...
s, 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, or UDP-glucose:glycoprotein glucosyltransferase, is a soluble enzyme resident in the lumen of the endoplasmic reticulum (ER).
The main function of UGGT is to recognize misfolded glycoproteins and transfer a glucose (Glc) monomer (monogluc ...
(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 and the expression of EDEM/Htm1p
which eventually sentences the underperforming glycoprotein to
degradation
Degradation may refer to:
Science
* Degradation (geology), lowering of a fluvial surface by erosion
* Degradation (telecommunications), of an electronic signal
* Biodegradation of organic substances by living organisms
* Environmental degradatio ...
by removing one of the nine
mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ...
residues. The mannose lectin Yos-9 (OS-9 in humans) marks and sorts misfolded glycoproteins for degradation. Yos-9 recognizes mannose residues exposed after α-mannosidase removal of an outer mannose of misfolded glycoproteins.
Calnexin associates with the protein folding enzyme ERp57
to catalyze glycoprotein specific disulfide bond formation and also functions as a chaperone for the folding of
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...
α-chain in the membrane of the ER. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.
After the β2-microglobulin binds to the MHC class I peptide-loading complex (PLC), calreticulin and ERp57 take over the job of chaperoning the MHC class I protein while the tapasin links the complex to the
transporter associated with antigen processing
Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
...
(TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
A prolonged association of calnexin with mutant misfolded
PMP22
Growth arrest-specific protein 3 (GAS-3), also called peripheral myelin protein 22 (PMP22), is a protein which in humans is encoded by the ''PMP22'' gene.
PMP22 is a 22 kDa transmembrane glycoprotein made up of 160 amino acids, and is mainly exp ...
known to cause
Charcot-Marie-Tooth Disease leads to the sequestration, degradation and inability of PMP22 to traffic to the
Schwann cell
Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...
surface for
myelination
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
. After repeated rounds of calnexin binding, mutant PMP22 is modified by
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
for degradation by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
as well as a Golgi to ER retrieval pathway to return any misfolded PMP22 that escaped from the ER to the Golgi apparatus.
The x-ray crystal structure of calnexin revealed a globular lectin domain and a long hydrophobic arm extending out.
Cofactors
ATP and
calcium ions
Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...
are cofactors involved in substrate binding for calnexin.
References
External links
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{{Membrane proteins
Integral membrane proteins
C-type lectins
Molecular chaperones