Sandbox Reserved 720: Difference between revisions

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'''Human Merlin FERM Domain'''

[[Image:structure2D.gif |thumb|left|230px|Human Merlin FERM Domains colored by chain]]

==Introduction ==

The merlin-1 protein is encoded by the Neurofibromatosis-2(Nf2) gene. Mutations in the Nf2 gene lead to an inheritable autosomal dominant disorder : the Neurofibromatosis type 2. This desease is characterized by tumor proliferations as well in humans as in mice.

Patients develop tumors of the nervous system : meningiomas, schwannomas, neurofibromas.<ref>PMID:3125435</ref>

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 [http://swissvar.expasy.org/cgi-bin/swissvar/result?global_textfield=merlin 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 <ref>PMID:8242753</ref>.

Within this superfamily merlin-1 is closer to ezrin,radixin and moesin (the ERM proteins).

ERM proteins link adehrens 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 <ref>PMID:11329377</ref>.

===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 and 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<ref name="utile">PMID:20308985</ref>.

[[Image:imagevraie.gif |thumb|center|650px|Domain organization of ERM<ref name="utile" />]]

===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 also interacts with the FERM domain. 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>

The ERM proteins are regulated by changing from a close to an open conformation. 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 activate the proteins because they modify the intramolecular contacts, allowing them to bind to their partners. 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>.

===Regulators of the activity===

Phosphorylation of a C-terminal threonine by Rho kinase as well as 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>.

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>.

However Merlin-1 has some properties not shared with ERM proteins.

==Specificity of merlin FERM domain==

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

{{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>.

===Structural differences===

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" />.

The closed complex of 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>.

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" />. For more details about the probable quaternary states, see the [http://www.ebi.ac.uk/pdbe-srv/view/entry/3u8z/quaternary.html?global_textfield= PDBe page ]about the structure of 3u8z.

===Merlin regulation===

<scene name='Sandbox_Reserved_705/Jofre/1'>Ser-10</scene> and Ser-518 (not in the FERM domain) phosphorylations 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,reducing the inhibition of cell growth.

Merlin possess a serine 10 that can also be phosphorylated by Akt. This phosphorylation directs merlin for proteasome-mediated degradation.<ref>PMID:21750658</ref>.

===Tumor suppressive function===

The phosphoinositide 3-kinase PI3K/Akt signaling pathway is often involved in tumor proliferation. Indeed overexpression of Akt is associated with tumor development<ref>PMID:12094235</ref>. Merlin plays a fundamental role in controlling the PI3K/Akt pathway by inhibiting Akt signaling <ref>PMID:15598747</ref>.

Even if the precise mechanism is not known, CD44 is absolutely required for the growth suppressive function

of merlin. The protein interacts with CD44 (a transmembrane protein) but not through the same domain as ERM proteins. This interaction mediates merlin function and is regulated by the concentration of merlin in the cell and also through the concentration of hyaluronate (CD44 ligand). <ref>PMID:11316791</ref>.

===Applications===

Nowadays, late stage melanoma is resistant to any treatment. To achieve better therapies for patients, we need to get deeper in the understanding of the signaling pathways of melanoma progression. Merlin is a target that is seriously considered because its levels and activity can be modulated through post-translational modifications<ref>PMID:22912849</ref>.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.

A mechanism that lowers merlin expression in breast cancer<ref>PMID:21965655</ref> is the phosphorylation at <scene name='Sandbox_Reserved_705/Resi/1'>Thr-230</scene> and <scene name='Sandbox_Reserved_705/Rez/1'>Ser-315</scene>. They target the protein for ubiquitination,degradation <ref>PMID:17891137</ref>.

However there exist many proteins that regulate merlin expression. They may all be a useful therapetic target.Therefore further inverstigation are required to determine the pathways that involve the merlin protein.

== References ==

==External Resources==

* See: [[Oncogenes & Tumor Suppressor Genes]] for Additional examples of oncogenes and tumor suppressor genes.<br />

* See: [[Cancer]] for Additional Proteins involved in the disease. <br />

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@@ Line 2: / Line 2: @@
 {{Sandbox_ESBS_2012}}
 <!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
+'''Human Merlin FERM Domain'''
+[[Image:structure2D.gif |thumb|left|230px|Human Merlin FERM Domains colored by chain]]
+==Introduction ==
+The merlin-1 protein is encoded by the Neurofibromatosis-2(Nf2) gene. Mutations in the Nf2 gene lead to an inheritable autosomal dominant disorder : the Neurofibromatosis type 2. This desease is characterized by tumor proliferations as well in humans as in mice.
+Patients develop tumors of the nervous system : meningiomas, schwannomas, neurofibromas.<ref>PMID:3125435</ref>
+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 [http://swissvar.expasy.org/cgi-bin/swissvar/result?global_textfield=merlin 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 <ref>PMID:8242753</ref>.
+Within this superfamily merlin-1 is closer to ezrin,radixin and moesin (the ERM proteins).
+ERM proteins link adehrens 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 <ref>PMID:11329377</ref>.
+===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 and 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<ref name="utile">PMID:20308985</ref>.
+[[Image:imagevraie.gif |thumb|center|650px|Domain organization of ERM<ref name="utile" />]]
+===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 also interacts with the FERM domain. 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>
+The ERM proteins are regulated by changing from a close to an open conformation. 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 activate the proteins because they modify the intramolecular contacts, allowing them to bind to their partners. 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>.
+[[Image:inactivestate.gif |thumb|left|650px|Inactive ERM protein]][[Image:active2.gif |thumb|right|650px|Active ERM protein]]
+===Regulators of the activity===
+Phosphorylation of a C-terminal threonine by Rho kinase as well as 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>.
+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>.
+However Merlin-1 has some properties not shared with ERM proteins.
+==Specificity of merlin FERM domain==
+{{STRUCTURE_3u8z| PDB=3u8z | SCENE=| size='500'}}
+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
+{{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>.
+===Structural differences===
+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" />.
+The closed complex of 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>.
+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" />. For more details about the  probable quaternary states, see the [http://www.ebi.ac.uk/pdbe-srv/view/entry/3u8z/quaternary.html?global_textfield= PDBe page ]about the structure of 3u8z.
+===Merlin regulation===
+<scene name='Sandbox_Reserved_705/Jofre/1'>Ser-10</scene> and Ser-518 (not in the FERM domain) phosphorylations 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,reducing the inhibition of cell growth.
+Merlin possess a serine 10 that can also be phosphorylated by Akt. This phosphorylation directs merlin for proteasome-mediated degradation.<ref>PMID:21750658</ref>.
+===Tumor suppressive function===
+The phosphoinositide 3-kinase PI3K/Akt signaling pathway is often involved in tumor proliferation. Indeed overexpression of Akt is associated with tumor development<ref>PMID:12094235</ref>. Merlin plays a fundamental role in controlling the PI3K/Akt pathway by inhibiting Akt signaling <ref>PMID:15598747</ref>.
+Even if the precise mechanism is not known, CD44 is absolutely required for the growth suppressive function
+of merlin. The protein interacts with CD44 (a transmembrane protein) but not through the same domain as ERM proteins. This interaction mediates merlin function and is regulated by the concentration of merlin in the cell and also through the concentration of hyaluronate (CD44 ligand). <ref>PMID:11316791</ref>.
+===Applications===
+Nowadays, late stage melanoma is resistant to any treatment. To achieve better therapies for patients, we need to get deeper in the understanding of the signaling pathways of melanoma progression. Merlin is a target that is seriously considered because its levels and activity can be modulated through post-translational modifications<ref>PMID:22912849</ref>.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.
+A mechanism that lowers merlin expression in breast cancer<ref>PMID:21965655</ref> is the phosphorylation at <scene name='Sandbox_Reserved_705/Resi/1'>Thr-230</scene> and <scene name='Sandbox_Reserved_705/Rez/1'>Ser-315</scene>. They target the protein for ubiquitination,degradation <ref>PMID:17891137</ref>.
+However there exist many proteins that regulate merlin expression. They may all be a useful therapetic target.Therefore further inverstigation are required to determine the pathways that involve the merlin protein.
+== References ==
+<references/>
+==External Resources==
+* See: [[Oncogenes & Tumor Suppressor Genes]] for Additional examples of oncogenes and tumor suppressor genes.<br />
+* See: [[Cancer]] for Additional Proteins involved in the disease. <br />
+<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>
+<references group="xtra"/>