Sandbox Reserved 1712: Difference between revisions

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OCA, Jaime Prilusky, Hillary Kulavic, Andrew Peters, R. Jeremy Johnson

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 The value of the ALKr-ALKAL dimer is its rigidity and strength of its structure, being very important for the function of ALK. Each step of building from the ALK monomer to the dimer adds a level of strength in the structure, making it more likely to create the conformational change the kinase domain undergoes inside the cell across the membrane. This conformation into the dimer initiates a conformational change of the intracellular kinase domain of ALK. This causes an autophosphorylation of several tyrosine residues of this domain, which ultimately activates the kinase function of ALK and can now phosphorylate another protein or enzyme downstream in the signaling cascade. An example of a kinase that has a similar function to ALK are [https://proteopedia.org/wiki/index.php/Insulin_receptor#:~:text=The%20insulin%20receptor%20binds%20the,including%20skeletal%20muscle%20and%20adipose. insulin receptors] (IR). Their ligand (insulin) initiates a conformational change, which allows the kinase domain to be autophosphorylated, activating IR and allowing it to activate other enzymes or proteins down multiple possible signaling pathways via phosphorylation.
 == Disease ==
-Many <scene name='90/904317/Dimer_full_colored/9'>residual mutations</scene> have been identified that cause constitutive receptor activation. Enhanced receptor interaction or stabilization of active receptors also increase oncogenic potentials (Figure 3). The <scene name='90/904317/Dimer_full_colored/10'>His694</scene> that is mutated to arginine is known to be a gain-of-function mutation in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 3b). What causes this gain-of-function is the increased length of arginine compared to histidine, which allows it to interact with the other ALKr-ALKAL complex via ionic bonding. This creates a stronger interaction between the two complexes, which increases the likelihood for ALK to be activated at any given time, which then also keeps the whole signal pathway activated downstream. The <scene name='90/904317/Dimer_full_colored/11'>Gly474</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 3a), but this mutation would have a similar effect as His694Arg because it is an even bigger increase in length compared to the hydrogen side group of glycine. It is also a change from a nonpolar to a polar and charged side group, which will create ionic bonds with the other ALKr-ALKAL complex, making it an even bigger increase of interaction between the two complexes. The F856S and R753Q are two other mutations in ALK that are known to increase cytokine-dependent cell proliferation in certain cells. <ref>DOI:10.1038/s41586-021-03959-5</ref>
+Many <scene name='90/904317/Dimer_full_colored/9'>residual mutations</scene> have been identified that cause constitutive receptor activation. Enhanced receptor interaction or stabilization of active receptors also increase oncogenic potentials (Figure 3). One gain-of-function mutation found in [https://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung lung adenocarcinoma] is <scene name='90/904317/Dimer_full_colored/10'>His694</scene> that is mutated to arginine nd leads to constitutive activation of ALK (Fig. 3b). What causes this gain-of-function is the increased length of arginine compared to histidine, which allows it to interact with the other ALKr-ALKAL complex via ionic bonding. This creates a stronger interaction between the two complexes, which increases the likelihood for ALK to be activated at any given time, which then also keeps the whole signal pathway activated downstream. Mutation of <scene name='90/904317/Dimer_full_colored/11'>Gly474</scene> to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 3a), but this mutation would have a similar effect as His694Arg because it is an even bigger increase in length compared to the hydrogen side group of glycine. It is also a change from a nonpolar to a polar/charged side group, which will create ionic bonds with the other ALKr-ALKAL complex, making it an even bigger increase of interaction between the two complexes. The F856S and R753Q are two other mutations in ALK that are known to increase cytokine-dependent cell proliferation in certain cells. <ref>DOI:10.1038/s41586-021-03959-5</ref>
 [[Image:Screen Shot 2022-04-13 at 5.30.04 PM.png|800 px|left|thumb|Figure 3: Mutated residues on ALK that contribute to stabilization of the active state of ALK, leading to many types of cancers. A: Gly747Arg. B: His694Arg. [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
 </StructureSection>