Sandbox Reserved 1726: Difference between revisions

==== Three Helix Bundle-like Domain ====

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 dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" />

==== Poly-Glycine Domain ====

[[Image:glycinehelicesorange.png|300 px|right|thumb|Figure 2. Rare Glycine helices on Anaplastic Lymphoma Kinase; The structure of extracellular ALK is shown in a perpendicular, cross sectional way, highlighted in orange. In black, hydrogen bonds are structured in a hexagonal-like way. Made using [https://www.rcsb.org/structure/7N00 7N00]]]Located between the THB-like domain and the TNF-like domain, the <scene name='90/904331/Polyg_region1/4'>Poly-Glycine Region</scene> has an important structural role.<ref name="Reshetnyak" /> The GlyR domain also has a rare and unique structure of left-handed glycine helices with hexagonal hydrogen bonding (Figure 2).<ref name="Reshetnyak" /> These 14 glycine helices are unique to ALK's function among other tyrosine kinases.<ref name="Reshetnyak" /> These helices are rigid structures, providing a strong anchor for the ligand binding site while the other domains undergo conformational rearrangements.<ref name="Reshetnyak" />

==== Tumor-Necrosis Factor-like Domain ====

The <scene name='90/904331/Tnf-like_domain/2'>Tumor Necrosis Factor-like Domain</scene> interacts with the THB-like domain to begin the conformational changes associated with ligand binding.<ref name="Reshetnyak" /> Located in approximately the midregion of the extracellular region, the TNF-like domain bridges the gap between the GlyR domain and the EGF-like domain. The TNF-like domain also assists in mediating ligand binding with the EGF-like domain<ref name="Reshetnyak" /> by interacting with the THB-like domain to facilitate the critical conformation changes required for dimerization and ligand recognition.<ref name="Reshetnyak" />

==== Epidermal Growth Factor-like Domain ====

Unlike the poly-Glycine helices, the <scene name='90/904331/Egf_like_domain/3'>Epidermal Growth Factor-like Domain</scene> is malleable and repositioning of this domain is essential for activation of the protein.<ref name="Reshetnyak" /> This domain undergoes conformational changes upon ligand binding and when in contact with the TNF-like domain.<ref name="Reshetnyak" /> The interface between the EGF-like and TNF-like domains are primarily hydrophobic residues, which enables their flexibility with regards to one another.<ref name="Reshetnyak" /> Major motifs in the EGF-like domain are major and minor β-hairpins, which are stabilized by 3 conserved disulfide bridges. <ref name="Reshetnyak" />

== Extracellular Domain Binding ==

=== Ligands ===

==== ALKAL2 ====

<scene name='90/904331/Alkal2/3'>ALKAL2</scene> is a shared ligand of ALK and LTK. Dimeric ALKAL2 and monomeric ALKAL2-AD both induce dimerization of ALK <ref name="Reshetnyak">PMID:34819673</ref>. Structurally, ALKAL2 has an N-terminal variable region, a conserved augmentor domain, and tends to aggregate in the cell <ref name="Reshetnyak" />. Overexpression of ALKAL2 is linked to high-risk [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma] in absence of an ALK mutation <ref name="Borenas">PMID:33411331</ref>.

==== ALKAL1 ====

<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>

=== Binding Site ===

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" />

=== Dimerization of ALK ===

After binding to one of its ligands, ALK undergoes <scene name='90/904331/Alk_full_dimerization/3'>ligand-induced dimerization</scene> <ref name="Huang">PMID:30400214</ref>. The [https://en.wikipedia.org/wiki/Dimer_(chemistry) dimerization] causes trans-phosphorylation of specific [https://en.wikipedia.org/wiki/Tyrosine tyrosine] residues which in turn amplifies the signal. It has been presumed that the [https://en.wikipedia.org/wiki/Phosphorylation_cascade phosphorylation cascade] activates ALK kinase activity <ref name="Huang" />.