Sandbox Reserved 1713: Difference between revisions
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The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904318/Alk-alkal_binding_surface/2'>binding surface</scene> on the ALK at the TNFL domain. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward.<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2) ALK's TNFL has <scene name='90/904318/Binding_surface_with_residues/3'>residues</scene> E978, E974, E859, and Y966 that form salt bridges with R123, R133, R136, R140, and R117 on ALKAL that allow for activation, leading to <scene name='90/904317/Dimer_full_colored/3'>dimerization</scene> of two ALK-ALKAL monomers. | The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904318/Alk-alkal_binding_surface/2'>binding surface</scene> on the ALK at the TNFL domain. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward.<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2) ALK's TNFL has <scene name='90/904318/Binding_surface_with_residues/3'>residues</scene> E978, E974, E859, and Y966 that form salt bridges with R123, R133, R136, R140, and R117 on ALKAL that allow for activation, leading to <scene name='90/904317/Dimer_full_colored/3'>dimerization</scene> of two ALK-ALKAL monomers. | ||
===Membrane Guidance of ALKAL to ALK=== | ===Membrane Guidance of ALKAL to ALK=== | ||
The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904318/Alkalbindingsurfacewmembrane/1'>helix</scene> on ALKAL that faces the membrane. These <scene name='90/904318/Alkal1membraneinteraction/2'>residues that interact with the cell membrane</scene> guides ALKAL to ALK and correctly positions ALKAL for its <scene name='90/904318/Alk-alkal_binding_surface/ | The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904318/Alkalbindingsurfacewmembrane/1'>helix</scene> on ALKAL that faces the membrane. These <scene name='90/904318/Alkal1membraneinteraction/2'>residues that interact with the cell membrane</scene> guides ALKAL to ALK and correctly positions ALKAL for its <scene name='90/904318/Alk-alkal_binding_surface/4'>binding surface to face ALK's binding surface</scene>, which allows for a more favorable interaction. <ref>DOI: 10.1038/s41586-021-04140-8</ref> | ||
===Role of Activated ALK=== | ===Role of Activated ALK=== | ||
Once the ALKAL binds with ALK and dimerizes with another ALK-ALKAL complex, this activated conformation also initiates a conformational change of the intracellular kinase domain of ALK. This causes an autophosphorylation of several tyrosine residues of this domain, activating a signaling cascade with its kinase activity. | Once the ALKAL binds with ALK and dimerizes with another ALK-ALKAL complex, this activated conformation also initiates a conformational change of the intracellular kinase domain of ALK. This causes an autophosphorylation of several tyrosine residues of this domain, activating a signaling cascade with its kinase activity. | ||