Sandbox Reserved 705: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older edit
No edit summary
No edit summary
 
(41 intermediate revisions by 2 users not shown)
Line 4: Line 4:


''' Human Merlin FERM Domain'''
''' Human Merlin FERM Domain'''
<Structure load='3u8z' size='230' frame='true' align='left' caption='Human Merlin FERM Domain 3u8Z' scene='Insert optional scene name here' />


==Introduction ==
==Introduction ==
Line 15: Line 18:
ERM proteins link Adhrens Junctions to the actin cytoskeleton,and are able to remodel Adherens Junctions during epithelial morphogenesis.
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 <ref>PMID:11329377</ref>.
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. This domain is divided into three subdomains (F1, F2, and F3).
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<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===
The acitivity of ERM proteins is caused by the association of different regions within the protein.
The acitivity of ERM proteins is caused by the association of different regions within the protein.
'''Le domain FERM ne lie pas l'hélicale alpha? la head c pa le domaine FERM? Ce serait plus simple et il faudrai le citer pour que ça ait du sens'''
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>
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 first two of which bind lobe F2 and second two lobe F3. The FERM-tail complex represents a dormant 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 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>.
'''C'est ce que j'ai lu sur les ERM proteines mais après c'était l'un des points que j'avait pas trop compris All ERM proteins appear to be regulated by transitioning from a closed conformation to an open, active state following severing of intramolecular head–tail interactions, and of interactions between their head and central α-helical domains. The crystal structures of the FERM domains of ezrin and merlin,the moesin head:tail complex, and the moesin FERM domain in complex with its central α-helical domain have been solved. The moesin head:tail complex structure established that this interaction buries the charged F-actin binding site, and that the C-terminal tail covers large portions of the F2 and F3 motifs of the FERM domain. il sempblerait que la tete soit le C terminal mais je suis pas sur.'''
 
The ERM proteins are regulated by changing from a closed conformation to an open, active state. This is due to intramolecular head–tail interactions,and also to interactions between their head and α-helical domains<ref name="utile2">PMID:22012890</ref>.Conformational changes modify the intramolecular contacts, allowing these proteins to bind to their partners.
[[Image:inactivestate.gif |thumb|left|650px|Inactive ERM protein]][[Image:active2.gif |thumb|right|650px|Active ERM protein]]
Phosphorylation of a C-terminal threonine by Rho kinase and binding to phosphatidylinositol 4,5-bisphosphate 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.
 
'''On précise que c'est le binding de PIP2 ?'''<ref>PMID:21402777</ref>
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
===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 <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>.
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.  
However Merlin-1 has some properties not shared with ERM proteins.  
'''Further, the binding of a basic cleft that lies between the F1 and F3 subdomains to phosphatidylinositol 4,5-bisphosphate (PIP2) directs ERM proteins to the plasma membrane, and may also sever their head–tail interactions. '''
 


==Specificity of merlin FERM domain==
==Specificity of merlin FERM 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  
{{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>.
{{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===
===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 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 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>.
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>.
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" />. Ser-10 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.
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" />.
'''Revoir et compléter la dimérisation'''
===CD44===
===Merlin regulation===
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. Indeed, CD44 is a receptor presents in the TA3 carcinome mammaire cells and Tr6BC1 schwannoma cells and HA allows their growth.
<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.
'''Lire ces deux articles pour savoir s'il faut les citer<ref>PMID:11316791</ref><ref>PMID:9378774</ref>
 
Merlin possess a serine 10 that can 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 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>.
 
 
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> .
'''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>
<scene name='Sandbox_Reserved_705/Global/4'>charged</scene>
<scene name='Sandbox_Reserved_705/Global/4'>charged</scene>
<scene name='Sandbox_Reserved_705/Sheet/3'>hydrophobic,polar</scene>
<scene name='Sandbox_Reserved_705/Sheet/3'>hydrophobic,polar</scene
{{Template:ColorKey_Hydrophobic}} repartition  {{Template:ColorKey_Polar}} Savoir si on montre les hydrophobes etc et leur intérêt...puisqu'on a leur répartition. Faire un schéma pour la structural difference de merlin et ERM protein pour montrer que c'est plus court. Décrire CD44 role. Qu'ajouter de plus? As tu des idées de schémas que l'on peut faire ou imiter à partir d'une publi ou je sais pas? As tu des idées de structure 3D que l'on peut montrer? Peux tu me dire s'il y a des fautes dans le texte en anglais ( ce qui est le cas je le sais^^) j'ai pas encore tout relu je regardais les deux auttres articles et cherchais les réponses à tes questions ^^'''
===Applications===
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.
Merlin is a target that is seriously considered.
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.
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>.
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.


===Applications===
'''J'ai trouvé un article la dessus enfin qui l'évoque^^ je rédigerais ça demain ou bientôt^^ ok donne moi l'article si tu veux que je le fasse car je vois que tu as passé pas mal de temps déjà sur ça XD'''


== References ==
== References ==
Retrieved from "https://proteopedia.org/Sandbox_Reserved_705"