Sandbox Reserved 1713: Difference between revisions
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[[Image:Prote_ALK_Monomer_White.png|400 px|right|thumb|Figure 1: The ALK monomer unbound to ALKAL. Cyan: growth factor-like domain (EGF). Orange: tumor necrosis factor-like domain (TNFL). Green: glycine-rich domain (GlyR). Pink: polyglycine extension loop (PXL).]] | [[Image:Prote_ALK_Monomer_White.png|400 px|right|thumb|Figure 1: The ALK monomer unbound to ALKAL. Cyan: growth factor-like domain (EGF). Orange: tumor necrosis factor-like domain (TNFL). Green: glycine-rich domain (GlyR). Pink: polyglycine extension loop (PXL).]] | ||
The domains that aren't shown in Figure 1 but are shown in the domain map (Figure 2) that also make up the monomer are the heparin binding domains (HBDs), which are at the N-terminal end of the monomer. Heparin has been found to be a possible activating ligand of ALK.<ref>DOI: 10.1126/scisignal.2005916</ref> The transmembrane domain (TMH) are the residues of ALK that are located within the membrane. The kinase domain is the intracellular portion of ALK that contains the Tyr residues which are auto-phosphorylated when ALK is activated, initiating a signaling cascade. | The domains that aren't shown in Figure 1 but are shown in the domain map (Figure 2) that also make up the monomer are the heparin binding domains (HBDs), which are at the N-terminal end of the monomer. Heparin has been found to be a possible activating ligand of ALK.<ref>DOI: 10.1126/scisignal.2005916</ref> The transmembrane domain (TMH) are the residues of ALK that are located within the membrane. The kinase domain is the intracellular portion of ALK that contains the Tyr residues which are auto-phosphorylated when ALK is activated, initiating a signaling cascade. | ||
[[Image:Proteo_ALK-ALKAL_Monomer_White.png|400 px|right|thumb|Figure 2: ALK-ALKAL complex, showing the conformation change of ALK from the binding of ALKAL.]] | |||
[[Image:Proteo_ALK-ALKAL_Monomer_White.png|400 px|right|thumb|Figure 2 | |||
===Conformational Change=== | ===Conformational Change=== | ||
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 binding surface to face ALK's binding surface, which allows for a more favorable interaction. <ref>DOI: 10.1038/s41586-021-04140-8</ref> | 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 binding surface to face ALK's binding surface, which allows for a more favorable interaction. <ref>DOI: 10.1038/s41586-021-04140-8</ref> | ||
== | ===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. | |||
There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials. | There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials. | ||
<scene name='90/904318/Premutationresidues/2'>mutated residues</scene> | <scene name='90/904318/Premutationresidues/2'>mutated residues</scene> | ||