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 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 Moesin is a protein that in humans is encoded by the ''MSN'' gene. Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers b ...

Ezrin Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the ''EZR'' gene. Structure The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contain an ERM d ...

Radixin Radixin is a protein that in humans is encoded by the ''RDX'' gene. Radixin is a cytoskeletal protein that may be important in linking actin to the plasma membrane. It is highly similar in sequence to both ezrin and moesin. The radixin gene has ...

-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 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 Protein 4.1, also known as Beatty's Protein, is a protein associated with the cytoskeleton that in humans is encoded by the ''EPB41'' gene. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in reg ...

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 A schwannoma (or neurilemmoma) is a usually benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves. Schwannomas are homogeneous tumors, consisting only of Schwann cells. ...

Structure

Vertebrate merlin is a 70

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

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 A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

-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 A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

tissues, and is mainly located in

adherens junction Adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions, cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. ...

s. 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 gland The salivary glands in mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands (parotid, submandibular, and sublingual), as well as hundreds of minor salivary glands. Salivary gla ...

s, and

imaginal disc An imaginal disc is one of the parts of a holometabolous insect larva that will become a portion of the outside of the adult insect during the pupal transformation. Contained within the body of the larva, there are pairs of discs that will form, ...

s, 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 ...

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 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhesi ...

protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...

, 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 ...

, 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 schwannoma A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the inner ear to the brain. The tumor originates when Schwann cells that form the insulating myelin sheath o ...

s (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