Sandbox Reserved 971: Difference between revisions

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[http://www.ncbi.nlm.nih.gov/gene/90865 Interleukin 33] is a cytokine member of the [http://www.ncbi.nlm.nih.gov/pubmed/24677376 interleukin 1 superfamily]. Cytokines are proteins involved in cell signaling. Their role is to regulate the function and the activity of other cells. IL-33 is involved in innate and adaptive immune responses.  
[http://www.ncbi.nlm.nih.gov/gene/90865 Interleukin 33] is a cytokine member of the [http://www.ncbi.nlm.nih.gov/pubmed/24677376 interleukin 1 superfamily]. Cytokines are proteins involved in cell signaling. Their role is to regulate the function and the activity of other cells. IL-33 is involved in innate and adaptive immune responses.  


In 2005, IL-33 was identified as a ligand for the transmembrane receptor ST2 (also known as [http://www.ncbi.nlm.nih.gov/gene/9173 IL1RL1] and it IL-1 receptor accessory protein (IL-1RAcP), both members of the [http://www.ncbi.nlm.nih.gov/pubmed/17027517 interleukin-1 receptor family]. IL-33/ST2 signaling is involved in T-cell immune responses.  
In 2005, IL-33 was identified as a ligand for the transmembrane receptor ST2 (also known as [http://www.ncbi.nlm.nih.gov/gene/9173 IL1RL1] and it IL-1 receptor accessory protein (IL-1RAcP) as you see below, both members of the [http://www.ncbi.nlm.nih.gov/pubmed/17027517 interleukin-1 receptor family]. IL-33/ST2 signaling is involved in T-cell immune responses.  
[[Image:IL33_with_its_receptor.png|700px]]
 
 
We will focuse on the interaction bewteen IL33 and the ST2 ectodomain (as you can see <scene name='61/614056/Name_il33_st2/1'>here</scene>).
We will focuse on the interaction bewteen IL33 and the ST2 ectodomain (as you can see <scene name='61/614056/Name_il33_st2/1'>here</scene>).


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IL-33 interacts with the ectodomain of ST2L on Th2 cells. This interaction provokes the recruitment of the myeloid differentiation primary-response protein 88 ([http://www.uniprot.org/uniprot/Q99836 MYD88]) complex, which is involved in the immune response against commune viral infections and some bacterial infections.
IL-33 interacts with the ectodomain of ST2L on Th2 cells. This interaction provokes the recruitment of the myeloid differentiation primary-response protein 88 ([http://www.uniprot.org/uniprot/Q99836 MYD88]) complex, which is involved in the immune response against commune viral infections and some bacterial infections.
When IL-33 interacts with the sST2, it inhibits the fixation of IL-33 of the ectodomain of ST2.
When IL-33 interacts with the sST2, it inhibits the fixation of IL-33 with the ectodomain of ST2.




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The understanding of the interaction of IL-33 with its receptors has been discovered thanks to the determination of the crystal structure of IL-33 in complex with ectodomain of ST2.  
The understanding of the interaction of IL-33 with its receptors has been discovered thanks to the determination of the crystal structure of IL-33 in complex with ectodomain of ST2.  


Besides, the combination of crystallography and small-angle X-ray-scattering methods reveal that ST2 has a very flexible conformation, contrary to IL-1RAcP. In fact, ST2 is constituted of three IgG-like domains (<scene name='61/614056/Domains_d1d2d3_de_st2/1'>D1 to D3</scene>). D1 and D2 gather to form a single D1D2 module, connected through a linker with the D3 domain. ST2 contains also <scenename='61/614056/Three_residues_of_st2_with_nag/3'>three residues</scene> linked with NAG and an <scene name='61/614056/St2_hydrophobic_patch/1'>hydrophobic patch</scene> which is involved in the interaction with the other receptor, IL-1RAcP.
Besides, the combination of crystallography and small-angle X-ray-scattering methods reveal that ST2 has a very flexible conformation, contrary to IL-1RAcP. In fact, ST2 is constituted of three IgG-like domains (<scene name='61/614056/Domains_d1d2d3_de_st2/1'>D1 to D3</scene>). D1 and D2 gather to form a single D1D2 module, connected through a linker with the D3 domain. The flexibility of these domains allows ST2 to exist in three different conformers, as you can see on the image below.
[[Image:ST2_conformers.png|600px ]]
 
On the left and on the right, there are respectively the open conformer and the close conformer of ST2. On the middle, the half-open conformer is shown. This conformer superimposes perfectly with the conformation of ST2 bound with IL-33.  


This conformational specificity provides a capactity of ligand-binding with IL-33. Moreover, the rigidity of IL-1RAcP explains that it can not bind the IL-33 ligand directly.
This conformational specificity provides a capactity of ligand-binding with IL-33. Moreover, the rigidity of IL-1RAcP explains that it can not bind the IL-33 ligand directly.
ST2 contains also <scene name='61/614056/Three_residues_of_st2_with_nag/3'>three residues</scene> linked with NAG and an <scene name='61/614056/St2_hydrophobic_patch/1'>hydrophobic patch</scene> which is involved in the interaction with the other receptor, IL-1RAcP.


In humans, IL-33 in its full length is composed of 270 residues and is biologically active.
In humans, IL-33 in its full length is composed of 270 residues and is biologically active.
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In the complex, IL-33 interacts with the three domains of ST2. The binding interface is very large and composed of two separate sites.  
In the complex, IL-33 interacts with the three domains of ST2. The binding interface is very large and composed of two separate sites.  


In the <scene name='61/614056/Interaction_site_1/7'>first binding site</scene>, thirteen IL-33 residues from β-loops are in contact with the D1D2 module of ST2: the four marked acids residues of IL-33 form a salt-bridge with five marked ST2 residues respectively. Besides, Glu144 and Asp149 form hydrogen bonds with main-chain atoms of ST2. IL-33 mutation of one of the acid residues (144, 148, 149 and 244) highly decreases the affinity of ST2 for IL-33.
In the <scene name='61/614056/Interaction_site_1/7'>first binding site</scene>, thirteen IL-33 residues from β-loops are in contact with the D1D2 module of ST2: the four marked acids residues of IL-33 form a salt-bridge with five marked ST2 residues respectively. Besides, <scene name='61/614056/Il3_and_st2_with_two_colors/4'>Glu 144 and Asp149</scene> form hydrogen bonds with main-chain atoms of ST2. IL-33 mutation of one of the acid residues (144, 148, 149 and 244) highly decreases the affinity of ST2 for IL-33.


In the <scene name='61/614056/Interaction_site_2/3'>second binding site</scene>, eight IL-33 residues from β-strands interact with the D3 domain of ST2.  
In the <scene name='61/614056/Interaction_site_2/3'>second binding site</scene>, eight IL-33 residues from β-strands interact with the D3 domain of ST2.  


There are both hydrophobic and hydrophilic interactions. Residues of IL-33 form an hydrophobic cluster (IL-33 residues Tyr163 and Leu182 and ST2 residues Leu246, Leu306, and Leu311). A salt-bridge interaction occurs between acidic residue Glu165 and Arg313 of ST2.
There are both hydrophobic and hydrophilic interactions. Residues of IL-33 form an hydrophobic cluster (IL-33 residues Tyr163 and Leu182 and ST2 residues Leu246, Leu306, and Leu311). A salt-bridge interaction occurs between acidic residue <scene name='61/614056/Il3_and_st2_with_two_colors/5'>Glu 165 and Arg 313</scene> respectivevly of IL-33 and ST2.




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