Sandbox Reserved 1705: Difference between revisions

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=== Ligand Binding===
=== Ligand Binding===
  [[Image:ALK Conformational Change Gif.gif|850 px|right|thumb|Figure 3: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand-binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]  
  [[Image:ALK Conformational Change Gif.gif|850 px|right|thumb|Figure 3: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand-binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]  
The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and <scene name='90/904310/Ligand/2'>AUG</scene> in a dimeric fashion <ref name="Li">PMID:34819665</ref> . Its biologically preferred ligand is AUG, a 128 monomer peptide ligand. FAM150 is a structural ortholog of AUG. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 3). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/5'>bound</scene> (Step 2, Figure 3), ALK undergoes a conformational change and folds over so that the <scene name='90/904310/Positive_residues/1'>positively charged residues</scene> on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane (Step 3, Figure 3). The residues of ALK and it's ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/5'>salt bridges</scene><ref name="Munck">PMID:34646012</ref>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer. Another well-known RTK is the insulin receptor which is activated using a similar pathway. To learn more about the larger mechanism of RTK activation, click [https://proteopedia.org/wiki/index.php/Insulin_receptor#:~:text=The%20insulin%20receptor%20binds%20the,including%20skeletal%20muscle%20and%20adipose here].
ALKALs recognized by ALK are FAM150, binding in either a monomeric or dimeric fashion, and <scene name='90/904310/Ligand/2'>AUG</scene> in a dimeric fashion <ref name="Li">PMID:34819665</ref> . Its biologically preferred ligand is AUG, a protein ligand containing 128 residues that form three α-helices. FAM150 is a structural ortholog of AUG. The binding of ALK to it's ligand results in homodimerization and an induced conformational change. Prior to the ligand binding to ALK, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 3). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/5'>bound</scene> (Step 2, Figure 3), ALK undergoes a conformational change and folds over so that the <scene name='90/904310/Positive_residues/1'>positively charged residues</scene> on the ALKAL can now interact with the negatively charged phosphate heads of the plasma membrane (Step 3, Figure 3). The residues of ALK and its ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/5'>salt bridges</scene><ref name="Munck">PMID:34646012</ref>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand activation allows for the auto-activation of the kinase domain, where the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer. ALK is a Class II RTK ([[Insulin Receptor|Insulin Receptor family]]), sharing much of its kinase activation mechanism with the IR.




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