Sandbox Reserved 779: Difference between revisions

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relevant background:
==Relevant background ==


class of protein :Belongs to the calycin superfamily. Lipocalin family.
class of protein :Belongs to the calycin superfamily. Lipocalin family.
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organisms:These proteins are found in gram negative bacteria, vertebrate cells, and invertebrate cells, and in plants.  
organisms:These proteins are found in gram negative bacteria, vertebrate cells, and invertebrate cells, and in plants.  


other information: Subunit structure : Under physiological conditions beta-lactoglobulin exists as an equilibrium mixture of monomeric and dimeric forms.
==Subunit structure==
Under physiological conditions beta-lactoglobulin exists as an equilibrium mixture of monomeric and dimeric forms.
Subcellular location: Secreted.
Subcellular location: Secreted.
Tissue specificity: Synthesized in mammary gland and secreted in milk.
Tissue specificity: Synthesized in mammary gland and secreted in milk.
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===Structural organization===
===Contoh===
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).
C-terminal domain<ref name="utile">PMID:20308985</ref>.
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" />]]
[[Image:imagevraie.gif |thumb|center|650px|Domain organization of ERM<ref name="utile" />]]
===Regulation of the activity===
===Contoh===
The acitivity of ERM proteins is caused by the association of different regions within the protein.
The FERM-tail complex represents an inactive form of the protein in which membrane protein and active binding sites are masked.<ref>doi: 10.1074/jbc.274.1.170</ref>
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>doi: 10.1074/jbc.274.1.170</ref>
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>.
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]]
[[Image:inactivestate.gif |thumb|left|650px|Inactive ERM protein]][[Image:active2.gif |thumb|right|650px|Active ERM protein]]




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===Regulators of the activity===
===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>.
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>.
E-cadherin <ref>PMID:12695331</ref>.
However Merlin-1 has some properties not shared with ERM proteins.  
However Merlin-1 has some properties not shared with ERM proteins.  


merlin FERM


==Specificity of merlin FERM domain==
==Specificity of contoh domain==
{{STRUCTURE_3u8z| PDB=3u8z | SCENE=| size='500'}}
{{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  
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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===Structural differences===
===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.
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.


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Merlin possess a serine 10 that can also be phosphorylated by Akt. This phosphorylation directs merlin for proteasome-mediated degradation.<ref>PMID:21750658</ref>.   
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===
Merlin plays a fundamental role in controlling the PI3K/Akt pathway by inhibiting Akt signaling <ref>PMID:15598747</ref>.
 
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
Even if the precise mechanism is not known, CD44 is absolutely required for the growth suppressive function
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===Applications===
===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 an useful therapetic target.Therefore further inverstigation are required to determine the pathways that involve the merlin protein.


==External Resources==
==External Resources==
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