Sandbox Reserved 1712: Difference between revisions

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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 ==

~~There are many~~ <scene name='90/904317/~~Premutationresidues~~/1'>~~residues that could be mutated~~</scene> that ~~would~~ cause constitutive receptor activation~~, enhancement between the~~ interaction ~~of receptors~~ or stabilization of active receptors ~~are known to relate to~~ oncogenic potentials (Figure 4). The <scene name='90/904317/His694/2'>His694</scene> that is mutated to arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 4a). The <scene name='90/904317/Gly747/1'>Gly747</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 4b). The F856S and R753Q mutations 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). The <scene name='90/904317/His694/2'>His694</scene> that is mutated to arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 4a). The <scene name='90/904317/Gly747/1'>Gly747</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 4b). The F856S and R753Q mutations 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 4: Mutated residues on ALK that contribute to stabilization of the active state of ALK, leading to many types of cancers. From left to right: F856S, G747R, H694R, R753Q [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]

[[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. From left to right: F856S, G747R, H694R, R753Q [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]

</StructureSection>

== References ==

Sandbox Reserved 1712: Difference between revisions

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@@ Line 19: / Line 19: @@
 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 ==
-There are many <scene name='90/904317/Premutationresidues/1'>residues that could be mutated</scene> that would cause constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials (Figure 4). The <scene name='90/904317/His694/2'>His694</scene> that is mutated to arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 4a). The <scene name='90/904317/Gly747/1'>Gly747</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 4b). The F856S and R753Q mutations 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). The <scene name='90/904317/His694/2'>His694</scene> that is mutated to arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 4a). The <scene name='90/904317/Gly747/1'>Gly747</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 4b). The F856S and R753Q mutations 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 4: Mutated residues on ALK that contribute to stabilization of the active state of ALK, leading to many types of cancers. From left to right: F856S, G747R, H694R, R753Q [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
+[[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. From left to right: F856S, G747R, H694R, R753Q [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
 </StructureSection>
 == References ==