Sandbox Reserved 1712: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 10: Line 10:


The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK. The extracellular portion of ALK has an inactive state, which is its monomerized form, and an active dimerized state with its ligands bound. The monomer is shown in Figure 2, which has many different domains (Figure 1). The growth factor-like domain (EGF) connects the extracellular domains to the transmembrane domain (cyan). The tumor necrosis factor-like domain (TNFL) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand (orange). The glycine-rich domain (GlyR) contains 14 rare polyglycine helices that are hydrogen-bound to each other (green). The <scene name='90/904317/Glycinerichdomain/1'>hexagonal orientation</scene> of these rare helices create a very rigid structure that is important for ALK function. The polyglycine extension loop (PXL) connects two of these polyglycine helices (pink).
The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK. The extracellular portion of ALK has an inactive state, which is its monomerized form, and an active dimerized state with its ligands bound. The monomer is shown in Figure 2, which has many different domains (Figure 1). The growth factor-like domain (EGF) connects the extracellular domains to the transmembrane domain (cyan). The tumor necrosis factor-like domain (TNFL) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand (orange). The glycine-rich domain (GlyR) contains 14 rare polyglycine helices that are hydrogen-bound to each other (green). The <scene name='90/904317/Glycinerichdomain/1'>hexagonal orientation</scene> of these rare helices create a very rigid structure that is important for ALK function. The polyglycine extension loop (PXL) connects two of these polyglycine helices (pink).
[[Image:Prote_ALK_Monomer_White.png|400 px|right|thumb|Figure 2: 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). [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
 
The domains that aren't shown in Figure 2 but are shown in the domain map (Figure 1) also make up the monomer. The heparin binding domains (HBDs), 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) contains 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. <ref>DOI: 10.1038/s41586-021-04141-7</ref>
The domains that aren't shown in Figure 2 but are shown in the domain map (Figure 1) also make up the monomer. The heparin binding domains (HBDs), 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) contains 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. <ref>DOI: 10.1038/s41586-021-04141-7</ref>
[[Image:Proteo_ALK-ALKAL_Monomer_White.png|400 px|right|thumb|Figure 3: ALK-ALKAL complex, showing the conformation change of ALK from the binding of ALKAL. [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
[[Image:Conformational change 2D.png|400 px|right|thumb|Figure 3: ALK-ALKAL complex, showing the conformation change of ALK from the binding of ALKAL. [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]
===Conformational Change===
===Conformational Change===
The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904317/Alk-alkal_binding_surface/1'>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 3) ALK's TNFL has <scene name='90/904317/Binding_surface_with_residues/1'>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/5'>dimerization</scene> of two ALK-ALKAL monomers.
The anaplastic lymphoma kinase activating ligand (ALKAL) binds to the <scene name='90/904317/Alk-alkal_binding_surface/1'>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 3) ALK's TNFL has <scene name='90/904317/Binding_surface_with_residues/1'>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/5'>dimerization</scene> of two ALK-ALKAL monomers.
Retrieved from "https://proteopedia.org/Sandbox_Reserved_1712"