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ALKAL <scene name='90/904318/Dimer_full_colored/1'>binds</scene> to ALKr at the TNFL domain, which has important negatively charged residues that form <scene name='90/904317/Monomerfullcolor/11'>ionic bonds</scene> with positively charged residues on ALKAL. These bonds initiate the conformational change, as these residues can only come into close proximity with each other if the conformational change occurs. The PXL and GlyR domains hinge forward when the change is initiated<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2). Glu978, Glu974, Glu859, and Tyr966 are the residues of ALKr that form these bonds with Arg123, Arg133, Arg136, Arg140, and Arg117 of ALKAL. Once the ALKr-ALKAL complex is formed, the <scene name='90/904317/Dimer_full_colored/12'>dimerization</scene> of two ALKr-ALKAL complexes occurs. The main driving force of the interaction between two ALKr-ALKAL complexes that become a dimer are hydrophobic interactions of the PXL loop of one ALKr with the other complex's ALKAL and TNFL domain of ALKr. This dimer of two ALKr-ALKAL complexes is the active form of ALK and is now able to perform its main function of phosphorylation. | ALKAL <scene name='90/904318/Dimer_full_colored/1'>binds</scene> to ALKr at the TNFL domain, which has important negatively charged residues that form <scene name='90/904317/Monomerfullcolor/11'>ionic bonds</scene> with positively charged residues on ALKAL. These bonds initiate the conformational change, as these residues can only come into close proximity with each other if the conformational change occurs. The PXL and GlyR domains hinge forward when the change is initiated<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2). Glu978, Glu974, Glu859, and Tyr966 are the residues of ALKr that form these bonds with Arg123, Arg133, Arg136, Arg140, and Arg117 of ALKAL. Once the ALKr-ALKAL complex is formed, the <scene name='90/904317/Dimer_full_colored/12'>dimerization</scene> of two ALKr-ALKAL complexes occurs. The main driving force of the interaction between two ALKr-ALKAL complexes that become a dimer are hydrophobic interactions of the PXL loop of one ALKr with the other complex's ALKAL and TNFL domain of ALKr. This dimer of two ALKr-ALKAL complexes is the active form of ALK and is now able to perform its main function of phosphorylation. | ||
===Role and Function of Dimerized ALKr-ALKAL=== | ===Role and Function of Dimerized ALKr-ALKAL=== | ||
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. This makes it more likely to create the conformational change of the intracellular kinase domain. | 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. This makes it more likely to create the conformational change of the intracellular kinase domain. The conformational change of the dimer initiates a conformational change of the intracellular kinase domain of ALK, which causes an [https://en.wikipedia.org/wiki/Autophosphorylation autophosphorylation] of several tyrosine residues of this domain, ultimately activating the kinase function of ALK. | ||
The kinase domain 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 ([https://en.wikipedia.org/wiki/Insulin 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 == | == 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). 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> and it's mutated to arginine and leads to constitutive activation of ALK (Fig. 3b). The gain-of-function mutation is caused by 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/13'>Gly747</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. The change from a nonpolar to polar side group will create ionic bonds with the other ALKr-ALKAL complex, making it an even larger 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> and it's mutated to arginine and leads to constitutive activation of ALK (Fig. 3b). The gain-of-function mutation is caused by 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/13'>Gly747</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. The change from a nonpolar to polar side group will create ionic bonds with the other ALKr-ALKAL complex, making it an even larger 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> | ||