Merlin (also called Neurofibromin 2 or schwannomin) is a
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. In humans, it is a
tumor suppressor protein
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
involved in
neurofibromatosis type II
Neurofibromatosis type II (also known as MISME syndrome – multiple inherited schwannomas, meningiomas, and ependymomas) is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, ...
.
Sequence data reveal its similarity to the
ERM protein family
The ERM protein family consists of three closely related proteins, ezrin, radixin and moesin. The three paralogs, ezrin, radixin and moesin, are present in vertebrates, whereas other species have only one ERM gene. Therefore, in vertebrates these ...
.
The name "merlin" is an
acronym
An acronym is a word or name formed from the initial components of a longer name or phrase. Acronyms are usually formed from the initial letters of words, as in ''NATO'' (''North Atlantic Treaty Organization''), but sometimes use syllables, as ...
for "
Moesin-
Ezrin-
Radixin-Like Protein".
Gene
Human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
merlin is coded by the gene ''NF2'' in
Chromosome 22
Chromosome 22 is one of the 23 pairs of chromosomes in human cell (biology), cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and ...
.
Mouse
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
merlin gene is located on chromosome 11
and
rat
Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
merlin gene on chromosome 17.
Fruit fly merlin gene (symbol ''Mer'') is located on chromosome 1 and shares 58% similarity to its human
homologue.
Other merlin-like genes are known from a wide range of animals, and the derivation of merlin is thought to be in early
metazoa
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
. Merlin is a member of the ERM family of proteins including ezrin, moesin, and radixin, which are in the
protein 4.1 superfamily of proteins. Merlin is also known as ''schwannomin'', a name derived from the most common type of tumor in the NF2 patient phenotype, the
schwannoma.
Structure
Vertebrate merlin is a 70
kDa protein. There are 10 known
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
s of human merlin molecule (the full molecule being 595
amino acid
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 ...
s in length). The two most common of these are also found in the mouse and are called ''type 1'' and ''type 2'', differing by the absence or presence of
exon
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 sequen ...
16 or 17, respectively). All the known varieties have a conserved
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 ...
part, which contains a
FERM domain
In molecular biology, the FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane. FERM domains are found in a number of cytoskeletal-ass ...
(a domain found in most cytoskeletal-membrane organizing proteins). The FERM domain is followed by an
alpha-helical
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
domain and a
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are no ...
tail.
Merlin can
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
ize with itself and heterodimerize with other ERM family proteins.
Function
Merlin is a
membrane-cytoskeleton scaffolding protein, i.e. linking
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
filaments to cell membrane or membrane
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.
Human merlin is predominantly found in
nervous tissue
Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain ...
, but also in several other
fetal tissues, and is mainly located in
adherens junctions.
Its tumor suppressor properties are probably associated with
contact-mediated growth inhibition. ''Drosophila'' merlin is expressed in embryonic
hindgut
The hindgut (or epigaster) is the posterior ( caudal) part of the alimentary canal. In mammals, it includes the distal one third of the transverse colon and the splenic flexure, the descending colon, sigmoid colon and up to the ano-rectal juncti ...
,
salivary glands, and
imaginal discs, and has apparently a slightly different role than in vertebrates.
The
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
518 is known to alter the functional state of merlin.
The signaling pathway of merlin is proposed to include several salient cell growth controlling molecules, including eIF3c,
CD44,
protein kinase A, and
p21 activated kinase
p21 activated kinases (PAKs) are members of a family of enzymes. They serve as targets for the small GTP binding proteins CDC42 and Rac and have been implicated in a wide range of biological activities.
Members include:
* PAK1, regulating cell ...
s.
Work in ''Drosophila'' identified Merlin as an upstream regulator of the
Hippo tumor suppressor pathway
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its ke ...
, a function that is conserved in mammals. The Hippo pathway is a well conserved signalling pathway that coordinately regulates cell proliferation and apoptosis.
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s of the NF2 gene cause a human autosomal dominant disease called neurofibromatosis type 2. It is characterized by the development of tumors of the nervous system, most commonly of bilateral
vestibular schwannomas (also called acoustic neuromas). NF2 belongs to the
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
group of genes.
Interactions
Merlin (protein) has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
CUL4A
Cullin-4A is a protein that in humans is encoded by the ''CUL4A'' gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chro ...
,
*
DDB1
DNA damage-binding protein 1 is a protein that in humans is encoded by the ''DDB1'' gene.
Gene
The gene's position is on chromosome 11q12-q13.
Protein
The DDB1 gene encodes the large subunit of DNA damage-binding protein, a heterodimer composed ...
,
[
* EZR,]
* HGS,
* MED28
Mediator of RNA polymerase II transcription subunit 28 is an enzyme that in humans is encoded by the ''MED28'' gene. It forms part of the Mediator complex.
Function
Subunit Med28 of the Mediator may function as a scaffolding protein within ...
,
* RIT1
GTP-binding protein Rit1 is a protein that in humans is encoded by the ''RIT1'' gene.
Function
RIT belongs to the RAS (HRAS; MIM 190020) subfamily of small GTPases (Hynds et al., 2003). upplied by OMIMref name="entrez"/>
Clinical significanc ...
,[
* ]SDCBP
Syntenin-1 is a protein that in humans is encoded by the ''SDCBP'' gene.
Function
The protein encoded by this gene was initially identified as a molecule linking syndecan-mediated signaling to the cytoskeleton. The syntenin protein contains ta ...
,
* SPTBN1
Spectrin beta chain, brain 1 is a protein that in humans is encoded by the ''SPTBN1'' gene.
Function
Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the ...
, and
* VPRBP
Protein VPRBP is a protein that in humans is encoded by the ''VPRBP'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...
.[
]
References
External links
GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 2
{{PDB_Gallery, geneid=4771
Cytoskeleton
Peripheral membrane proteins
Human proteins
Tumor suppressor genes