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
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 ...
made up of 160
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
, and is mainly expressed in the
Schwann cells of the
peripheral nervous system. Schwann cells show high expression of PMP22, where it can constitute 2-5% of total protein content in compact
myelin. Compact myelin is the bulk of the peripheral
neuron's myelin sheath, a protective fatty layer that provides electrical insulation for the neuronal
axon.
The level of PMP22 expression is relatively low in the
central nervous system of adults.
Like other membrane proteins, newly translated PMP22 protein is temporarily sequestered to 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) and
Golgi apparatus for post-translational modifications. PMP22 protein is
glycosylated with an
N terminus-linked sugar and co-localized with the
chaperone protein calnexin in the ER.
After the protein is transported to the Golgi apparatus it can then become incorporated in the
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
of the cell.
Structure and function
In humans, the PMP22 gene is located on
chromosome 17p12 and spans approximately 40kb. The gene contains six
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
conserved in both humans and rodents, two of which are
5’ untranslated exons (1a and 1b) and result in two different
RNA transcripts with identical
coding sequences. The two transcripts differ in their 5' untranslated regions and have their own
promoter regulating expression. The remaining exons (2 to 5) include the coding region of the PMP22 gene, and are joined together after
post-transcriptional modification (i.e.
alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
).
The PMP22 protein is characterized by four
transmembrane domains, two extracellular loops (ECL1 and ECL2), and one intracellular loop.
ECL1 has been suggested to mediate a homophilic interaction between two PMP22 proteins, whereas ECL2 has been shown to mediate a heterophilic interaction between PMP22 protein and
Myelin protein zero
Myelin protein zero (P0, MPZ) is a single membrane glycoprotein which in humans is encoded by the ''MPZ'' gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by ...
(MPZ).
Although the PMP22 mechanism of action in myelinating Schwann cells is not fully known, it plays an essential role in the formation and maintenance of compact myelin.
When Schwann cells come into contact with a neuronal axon, expression of PMP22 is significantly
up-regulated,
whereas PMP22 is
down-regulated during axonal degeneration or transection.
PMP22 has shown association with
zonula-occludens 1 and
occludin, proteins that are involved in adhesion with other cells and the extracellular matrix, and also support functioning of myelin.
Along with cell adhesion function, PMP22 is also up-regulated during Schwann
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
, suggesting a role in
cell-cycle regulation
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subse ...
. PMP22 is detectable in non-neural tissues, where its expression has been shown to serve as growth-arrest-specific (gas-3) function.
Gene-dosage
Improper
gene dosage of the PMP22 gene can cause aberrant protein synthesis and function of myelin sheath. Since the components of myelin are
stoichiometrically
Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions.
Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equals ...
set, any irregular expression of a component can cause destabilization of myelin and neuropathic disorders.
Alterations of PMP22 gene expression are associated with a variety of neuropathies, such as
Charcot–Marie–Tooth type 1A (CMT1A),
Dejerine–Sottas disease
Dejerine–Sottas disease, also known as, Dejerine–Sottas neuropathy, progressive hypertrophic interstitial polyneuropathy of childhood and onion bulb neuropathy (and, ''hereditary motor and sensory polyneuropathy type III'' and ''Charcot–Marie ...
, and
Hereditary Neuropathy with Liability to Pressure Palsy
Hereditary neuropathy with liability to pressure palsy (HNPP) is a peripheral neuropathy, a condition that affects the nerves.update 2014 Pressure on the nerves can cause tingling sensations, numbness, pain, weakness, muscle atrophy and even paraly ...
(HNPP). Too much PMP22 (e.g. caused by
gene duplication
Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. ...
) results in CMT1A, and too little PMP22 (e.g. caused by
gene deletion) results in HNPP.
Gene duplication of PMP22 is the most common genetic cause of CMT
where the overproduction of PMP22 results in defects in multiple signalling pathways and dysfunction of
transcriptional factors like KNOX20,
SOX10 and
EGR2
Early growth response protein 2 is a protein that in humans is encoded by the ''EGR2'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation ...
.
Interactions
Peripheral myelin protein 22 has been shown to
interact with
myelin protein zero
Myelin protein zero (P0, MPZ) is a single membrane glycoprotein which in humans is encoded by the ''MPZ'' gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by ...
.
References
Further reading
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{{refend
External links
GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1