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Merlin shares certain properties with the ERM family : they both have a subcellular localization to cortical actin structures and they both bind to adhesion receptors.These receptors are CD44 <ref>PMID:9330869</ref> and E-cadherin <ref>PMID:12695331</ref>.
Merlin shares certain properties with the ERM family : they both have a subcellular localization to cortical actin structures and they both bind to adhesion receptors.These receptors are CD44 <ref>PMID:9330869</ref> and E-cadherin <ref>PMID:12695331</ref>.
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However Merlin-1 has some properties not shared with ERM proteins.
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However Merlin-1 has some properties not shared with ERM proteins.
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==Specificity of merlin FERM domain==
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{{STRUCTURE_3u8z| PDB=3u8z | SCENE=| size='500'}}
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As showed in the default scene, the structure 3U8Z has in total 4 chains. These are represented by 1 sequence-unique entity. The chains A,B and C possess 9
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{{Template:ColorKey_Helix}} and 15 {{Template:ColorKey_Strand}} and the chain D has only 9 {{Template:ColorKey_Helix}}and 14 {{Template:ColorKey_Strand}}. You can visualize their <scene name='Sandbox_Reserved_705/Hidoeurf/1'>repartition</scene>.
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===Structural differences===
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The overall architecture of merlin is similar to that of ERM proteins. Indeed they have almost the same organization : a FERM domain,a central α-helical rod, but lack a C-terminal actin-binding site<ref name= "utile2" />.
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The closed complex of the Merlin proteins corresponds to the tumor suppressor-active form. As the N-terminus FERM domain and C-terminus are maintained associated, Merlin is in a closed conformation and is able to promote nuclear translocation and inhibt growth<ref>PMID:22482125</ref>.
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More precisly,binding of the tail provokes dimerization and unfurling of the F2 motif of the FERM domain.The “closed” complex of merlin-1 is in fact an “open” dimer <ref name="utile" />.
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===Merlin regulation===
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<scene name='Sandbox_Reserved_705/Jofre/1'>Ser-10</scene> and Ser-518 phosphorylation by protein kinase A (PKA) and/or p21-activated kinase(PAK) trigger the "closed" complex <ref>PMID:18071304</ref>. Phosphorylation by PAK and PKA at Ser 518 renders the protein inactive, it reduces the inhibition of cell growth.
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Merlin possess a serine 10 that can be phosphorylated by Akt. This phosphorylation directs merlin for proteasome-mediated degradation.<ref>PMID:21750658</ref>.
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===Tumor suppressive function===
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The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is often involved in tumor proliferation.Indeed overexpression of Akt is often associated with tumor development<ref>PMID:12094235</ref>. Merlin plays a role in controlling the PI3K/Akt pathway by inhibiting Akt signaling <ref>PMID:15598747</ref>.
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CD44 is a cell-surface receptor for hyaluronan (HA a ligand). When HA binds to CD44 the complex promotes tumorigenesis it means it promotes tumor invasion and metastasis.<ref>PMID:11316791</ref> .
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'''Lire ces deux articles pour savoir s'il faut les citer le 14 c'est de celui ci que j'ai tirer les informations donc je pense que l'on doit le citer<ref>PMID:9378774</ref>
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<scene name='Sandbox_Reserved_705/Global/4'>charged</scene>
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<scene name='Sandbox_Reserved_705/Sheet/3'>hydrophobic,polar</scene
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===Applications===
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Nowadays, late stage melanoma is resistant to any treatment.To achieve better therapies for patients, we need to understand better the signaling pathways of melanoma progression.
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Merlin is a target that is seriously considered.
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Its levels and activity can be modulated through post-translational modifications<ref>PMID:22912849</ref>.
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Phosphorylation at Ser518 of merlin inactivates its growth inhibitive activity. As we explained this phosphorylation can be achieved by cyclic AMP-dependent protein PKA and PAK1.
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Phosphorylation of merlin at <scene name='Sandbox_Reserved_705/Resi/1'>Thr-230</scene> and <scene name='Sandbox_Reserved_705/Rez/1'>Ser-315</scene> target the protein for ubiquitination,degradation <ref>PMID:17891137</ref>.This is a mechanism that lowers merlin expression in breast cancer<ref>PMID:21965655</ref>.
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However there exist many protein that regulates merlin expression. They may be a useful therapetic target.Therefore scientist need to further inverstigate to determine the pathways that involve the merlin protein.
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== References ==
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<references/>
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==External Resources==
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<ref group="xtra">PMID:17134719</ref><ref group="xtra">PMID:22525268</ref><ref group="xtra">PMID:12356905</ref><ref group="xtra">PMID:12203111</ref><ref group="xtra">PMID:17134719</ref><ref group="xtra">PMID:14724586</ref><ref group="xtra">PMID:21402777</ref><ref group="xtra">PMID:10847681</ref>
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<references group="xtra"/>
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== Proteopedia Page Contributors and Editors ==
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[[User:Xavière Lornage|Xavière Lornage]] and [[User:Kéliann Lesault|Kéliann Lesault]]
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Revision as of 23:22, 23 December 2012



Human Merlin FERM Domain

Human Merlin FERM Domain 3u8Z

Drag the structure with the mouse to rotate

Contents

Introduction

The merlin-1 protein is encoded by the Neurofibromatosis-2(Nf2) gene. Neurofibromatosis type 2 is an inheritable autosomal dominant disorder. Patients develop tumors of the nervous system : meningiomas, schwannomas, neurofibromas.[1] Mutations in the Nf2 gene lead to tumor proliferation as well in humans as in mice. Therefore Merlin-1 is a tumor suppressor protein. To know more about the type of Nf2 mutations and the related deseases you can follow the link that leads you to the Portal to Swiss-Prot diseases and variants the Portal to Swiss-Prot diseases and variants

ERM Proteins

The merlin-1 protein belongs to the band 4.1 superfamily of membrane-cytoskeletal linkers [2]. Within this superfamily merlin-1 is closer to ezrin,radixin and moesin (the ERM proteins). ERM proteins link Adhrens Junctions to the actin cytoskeleton,and are able to remodel Adherens Junctions during epithelial morphogenesis. They also maintain the organization of apical surfaces on the plasma membrane [3].

Structural organization

All these proteins have an about 300-residue globular plasma membrane-associated FERM domain(four-point-one ezrin, radixin, moesin).This FERM domain is a highly conserved domain. This domain is divided into three subdomains (F1, F2, and F3). ERM proteins are composed of a FERM domain followed by a long region with a high α-helical propensity and terminating in a C-terminal domain[4].

Domain organization of ERM
Domain organization of ERM[4]

Regulation of the activity

The acitivity of ERM proteins is caused by the association of different regions within the protein. The C-terminal tail domain contains an F-actin binding site in the last 30 residues. This domain interacts with the FERM domain as an extended, meandering polypeptide beginning with a β-strand associated with β5 in F3 followed by four helices. The two first helices bind l and the two second lobe F3. The FERM-tail complex represents an inactive form of the protein in which membrane protein and active binding sites are masked.[5] The ERM proteins are regulated by changing from a closed conformation to an open, active state. This is due to severing of intramolecular head–tail interactions,and also of interactions between their FERM domain and α-helical domains[6].Conformational changes modify the intramolecular contacts, allowing these proteins to bind to their partners. The protein is in an active state.The FERM domain has a fundamental role because it allows ERM proteins to interact with integral proteins of the plasma membrane[7].

Inactive ERM protein
Inactive ERM protein
Active ERM protein
Active ERM protein











Regulators of the activity

Phosphorylation of a C-terminal threonine by Rho kinase and binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and protein partners, is necessary for full activation of ERM proteins [8]. They disrupt the head to tail interactions. The phosphorylations and/binding(s) determine the cellular localization and the cellular function of each specific ERM protein[9].



Merlin shares certain properties with the ERM family : they both have a subcellular localization to cortical actin structures and they both bind to adhesion receptors.These receptors are CD44 [10] and E-cadherin [11]. However Merlin-1 has some properties not shared with ERM proteins.

Proteopedia Page Contributors and Editors (what is this?)

Xavière Lornage, Kéliann Lesault

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