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=== Domains === | === Domains === | ||
==== Three Helix Bundle-like Domain ==== | ==== Three Helix Bundle-like Domain ==== | ||
The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function as it interacts with the TNF-like domain upon ligand binding. The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain. This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding. The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" /> | The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function as it interacts 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 rigorous 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 ==== | ==== 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.]]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. The GlyR domain also has a rare and unique structure of left-handed glycine helices with hexagonal hydrogen bonding shown in Figure 2. These 14 glycine helices are unique to ALK's function among other tyrosine kinases, as these types of structures on the binding domain are not present. These helices are rigid structures, providing a strong anchor for the ligand binding site while the other domains undergo drastic conformational rearrangements.<ref name="Reshetnyak" /> | [[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.]]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 shown in Figure 2.<ref name="Reshetnyak" /> These 14 glycine helices are unique to ALK's function among other tyrosine kinases, as these types of structures on the binding domain are not present.<ref name="Reshetnyak" /> These helices are rigid structures, providing a strong anchor for the ligand binding site while the other domains undergo drastic conformational rearrangements.<ref name="Reshetnyak" /> | ||
==== Tumor-Necrosis Factor-like Domain ==== | ==== 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. It is located in approximately the midregion of the extracellular region, bridging the gap between the GlyR domain and the EGF-like domain. This domain also assists in mediating ligand binding with the EGF-like domain. In ligand-binding, as previously stated, this domain interacts heavily with the THB-like domain to undergo critical conformation changes necessary for dimerization and ligand recognition. <ref name="Reshetnyak" /> | 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" /> It is located in approximately the midregion of the extracellular region, bridging the gap between the GlyR domain and the EGF-like domain. This domain also assists in mediating ligand binding with the EGF-like domain.<ref name="Reshetnyak" /> In ligand-binding, as previously stated, this domain interacts heavily with the THB-like domain to undergo critical conformation changes necessary for dimerization and ligand recognition. <ref name="Reshetnyak" /> | ||
==== Epidermal Growth Factor-like Domain ==== | ==== Epidermal Growth Factor-like Domain ==== | ||
The <scene name='90/904331/Egf_like_domain/3'>Epidermal Growth Factor-like Domain</scene> is very malleable and repositioning of this domain is essential for activation of the protein. This domain is able to undergo conformational changes with the ligand bound and when in contact with the TNF-like domain. The interface between the EGF-like and TNF-like domains are primarily hydrophobic residues, which enable their flexibility with regards to one another. The main motifs that are apart of the EGF-like domain are major and minor β-hairpins, which are stabilized by 3 conserved disulfide bridges. <ref name="Reshetnyak" /> | The <scene name='90/904331/Egf_like_domain/3'>Epidermal Growth Factor-like Domain</scene> is very malleable and repositioning of this domain is essential for activation of the protein.<ref name="Reshetnyak" /> This domain is able to undergo conformational changes with the ligand bound 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 enable their flexibility with regards to one another.<ref name="Reshetnyak" /> The main motifs that are apart of the EGF-like domain are major and minor β-hairpins, which are stabilized by 3 conserved disulfide bridges. <ref name="Reshetnyak" /> | ||
=== Binding Site === | === Binding Site === | ||
This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead the proximity of the ligand allows [https://en.wikipedia.org/wiki/Conformational_change conformational changes] across the protein. The ligands for ALK both 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 form are formed as the ligand approaches connecting the ligand with the receptor. 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 allow the drastic conformational changes in the extracellular domain that induce the signaling pathway. <ref name="Reshetnyak" /> | This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead the proximity of the ligand allows [https://en.wikipedia.org/wiki/Conformational_change conformational changes] across the protein. The ligands for ALK both 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 form are formed as the ligand approaches connecting the ligand with the receptor. 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 allow the drastic conformational changes in the extracellular domain that induce the signaling pathway. <ref name="Reshetnyak" /> | ||