Sandbox Reserved 1726: Difference between revisions

The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> performs a structural function by interacting with the TNF-like domain upon ligand binding.<ref name="Reshetnyak" /> The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain.<ref name="Reshetnyak" /> This outermost region of the extracellular ligand-binding domain undergoes substantial structural reorientation upon ligand binding.<ref name="Reshetnyak" /> The THB-like is primarily involved in the <scene name='90/904332/Thb-like_tnf-like_interface/1'>dimerization motif</scene> of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" />

<scene name='90/904331/Alkal1/5'>ALKAL1</scene> is a monomeric ligand of ALK. Structurally, ALKAL1 shares the same architecture as ALKAL2 with an N-terminal variable region and a conserved C-terminal augmentor domain <ref name="Reshetnyak" />. However, in ALKAL1, the N-terminal variable region is shorter, and has limited sequence similarity to ALKAL2. Overall, ALKAL1 still shares 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface for ligand binding <ref name="Reshetnyak" />. ALKAL1 as a monomer, however, binds to ALK with poor stability<ref name ="Chen">PMID:33391411</ref> and was only found to stimulate ALK dimerization at much higher concentrations than ALKAL2.<ref name="Reshetnyak2">PMID:26630010</ref>

The binding site is located on the TNF-like region. <ref name="DeMunck">PMID:34646012</ref> This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead the ligand binding initiates [https://en.wikipedia.org/wiki/Conformational_change conformational changes] across the protein. The ligands for ALK have highly positively charged faces that interact with the TNF-like region, the primary ligand-binding site on the extracellular region<ref name="Li" />. [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) Salt bridges] between the positively charged residues on the ligand and negatively charged residues on the receptor are stabilized by ligand binding. Three of these <scene name='90/904331/Salt_bridge_overview/1'>salt bridges</scene> occur between <scene name='90/904331/Salt_bridge_859_140/3'>E859 and R140</scene>, <scene name='90/904331/Salt_bridge_974_136/4'>E974 and R136</scene>, and <scene name='90/904331/Salt_bridge_978_123_133/3'>E978 with both R123 and R133</scene>. These strong ionic interactions also induce the conformational changes in the extracellular domain that induce the signaling pathway. <ref name="Reshetnyak" />