Xavière Lornage/Sandbox1

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==ERM Proteins==
 
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The merlin-1 protein belongs to the band 4.1 superfamily of membrane-cytoskeletal linkers <ref>PMID:8242753</ref>.
 
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Within this superfamily merlin-1 is closer to ezrin,radixin and moesin (the ERM proteins).
 
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ERM proteins link Adhrens Junctions to the actin cytoskeleton,and are able to remodel Adherens Junctions during epithelial morphogenesis.
 
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They also maintain the organization of apical surfaces on the plasma membrane <ref>PMID:11329377</ref>.
 
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===Structural organization===
 
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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).
 
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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<ref name="utile">PMID:20308985</ref>.
 
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[[Image:imagevraie.gif |thumb|center|650px|Domain organization of ERM<ref name="utile" />]]
 
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===Regulation of the activity===
 
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The acitivity of ERM proteins is caused by the association of different regions within the protein.
 
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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.<ref>PMID:17134719</ref>
 
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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<ref name="utile2">PMID:22012890</ref>.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<ref>PMID:12154370</ref>.
 
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[[Image:inactivestate.gif |thumb|left|650px|Inactive ERM protein]][[Image:active2.gif |thumb|right|650px|Active ERM protein]]
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''' Human Merlin FERM Domain'''
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<Structure load='3u8z' size='230' frame='true' align='left' caption='Human Merlin FERM Domain 3u8Z' scene='Insert optional scene name here' />
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==Introduction ==
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The merlin-1 protein is encoded by the Neurofibromatosis-2(Nf2) gene. Neurofibromatosis type 2 is an inheritable autosomal dominant disorder.
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Patients develop tumors of the nervous system : meningiomas, schwannomas, neurofibromas.<ref>PMID:3125435</ref>
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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 [http://swissvar.expasy.org/cgi-bin/swissvar/result?global_textfield=merlin the Portal to Swiss-Prot diseases and variants ]
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===Regulators of the activity===
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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 <ref>PMID:14993232</ref>. 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<ref>PMID:21402777</ref>.
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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>.
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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 23:21, 23 December 2012



Human Merlin FERM Domain

Human Merlin FERM Domain 3u8Z

Drag the structure with the mouse to rotate

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

Proteopedia Page Contributors and Editors (what is this?)

Xavière Lornage, Kéliann Lesault

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