Sandbox Reserved 1712: Difference between revisions

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

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 ===Membrane Guidance of ALKAL to ALK===
-The first step to the activation of ALK is to bind the ALK activating ligand (ALKAL) to ALKr. <scene name='90/904317/Monomerfullcolor/9'>ALKAL</scene> is a triple alpha-helix polypeptide structure that signals for a conformational change of ALK. The cell membrane allows for the interaction between the ALKAL and ALKr. The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904317/Monomerfullcolor/10'>alpha-helix</scene> on ALKAL that faces the membrane. These <scene name='90/904317/Alkal1membraneinteraction/5'>residues</scene> [https://www.rcsb.org/structure/7MZZ (7MZZ)] (Lys96, His99, Lys100) guide ALKAL to ALKr and correctly positions ALKAL for its binding surface to face ALKr's ligand site, which allows for a more favorable interaction. This interaction causes a conformational change, forming the <scene name='90/904317/Monomerfullcolor/12'>ALKr-ALKAL complex</scene>.
+The first step to the activation of ALK is to bind the ALK activating ligand (ALKAL) to ALKr. <scene name='90/904317/Monomerfullcolor/9'>ALKAL</scene> is a triple alpha-helix polypeptide structure that signals for a conformational change of ALK. The cell membrane allows for the interaction between the ALKAL and ALKr. The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904317/Monomerfullcolor/10'>alpha-helix</scene> on ALKAL that faces the membrane. These <scene name='90/904317/Alkal1membraneinteraction/7'>residues</scene> (Lys96, His99, Lys100) guide ALKAL to ALKr and correctly positions ALKAL for its binding surface to face ALKr's ligand site, which allows for a more favorable interaction. This interaction causes a conformational change, forming the <scene name='90/904317/Monomerfullcolor/12'>ALKr-ALKAL complex</scene>.
 ===Conformational Change===
-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 ALK-ALKAL complexes occurs. The main driving force of the interaction between two ALK-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 ALK-ALKAL complexes is the active form of ALK, and it 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===
 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.