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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 overall as it interacts with the | The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function overall 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" /> | ||
==== Poly-Glycine Domain ==== | ==== Poly-Glycine Domain ==== | ||
[[Image:glycinehelicesorange.png|300 px|right|thumb|Figure 2. Rare Glycine helices on Anaplastic Lymphoma Kinase]]Located between the | [[Image:glycinehelicesorange.png|300 px|right|thumb|Figure 2. Rare Glycine helices on Anaplastic Lymphoma Kinase]]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" /> | ||
==== 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 | 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" /> | ||
==== Epidermal Growth Factor-like Domain ==== | ==== Epidermal Growth Factor-like Domain ==== | ||
The <scene name='90/904331/Egf_like_domain/2'>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 | The <scene name='90/904331/Egf_like_domain/2'>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" /> | ||
=== 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 salt bridges 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 salt bridges 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" /> | ||
=== Ligands === | === Ligands === | ||
The extracellular ligands of | The extracellular ligands of ALK are ALKAL2 and ALKAL1. | ||
==== ALKAL2 ==== | ==== ALKAL2 ==== | ||
<scene name='90/904331/Alkal2/3'>ALKAL2</scene> (Anaplastic Lymphoma Kinase Ligand 2) is a ligand of ALK as well as LTK located in the extracellular region. The full-length ALKAL2 (dimeric) and ALKAL2-AD (monomeric) can both induce dimerization of ALK <ref name="Reshetnyak">PMID:34819673</ref>. Structurally, ALKAL2 has a N-termical variable region and a conserved augmentor domain and tends to aggregate in the cell <ref name="Reshetnyak" />. Overexpression of ALKAL2 has been linked to high-risk [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma] in absence of an ALK mutation <ref name="Borenas">PMID:33411331</ref> and could potentially have therapeutic opportunities. | <scene name='90/904331/Alkal2/3'>ALKAL2</scene> (Anaplastic Lymphoma Kinase Ligand 2) is a ligand of ALK as well as LTK located in the extracellular region. The full-length ALKAL2 (dimeric) and ALKAL2-AD (monomeric) can both induce dimerization of ALK <ref name="Reshetnyak">PMID:34819673</ref>. Structurally, ALKAL2 has a N-termical variable region and a conserved augmentor domain and tends to aggregate in the cell <ref name="Reshetnyak" />. Overexpression of ALKAL2 has been linked to high-risk [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma] in absence of an ALK mutation <ref name="Borenas">PMID:33411331</ref> and could potentially have therapeutic opportunities. | ||
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<scene name='90/904331/Alkal1/5'>ALKAL1</scene> (Anaplastic Lymphoma Kinase Ligand 1) is a monomeric ligand of ALK, in addition to ALKAL2. Structurally, ALKAL1 and ALKAL2 contain an N-terminal variable region and a conversed C-terminal augmentor domain <ref name="Reshetnyak" />. However, in ALKAL1, this N-terminal variable region is shorter, and shares no similar sequences to ALKAL2. Nevertheless, ALKAL1 shares a 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface which is used in ligand binding <ref name="Reshetnyak" />. | <scene name='90/904331/Alkal1/5'>ALKAL1</scene> (Anaplastic Lymphoma Kinase Ligand 1) is a monomeric ligand of ALK, in addition to ALKAL2. Structurally, ALKAL1 and ALKAL2 contain an N-terminal variable region and a conversed C-terminal augmentor domain <ref name="Reshetnyak" />. However, in ALKAL1, this N-terminal variable region is shorter, and shares no similar sequences to ALKAL2. Nevertheless, ALKAL1 shares a 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface which is used in ligand binding <ref name="Reshetnyak" />. | ||
=== Dimerization of Anaplastic Lymphoma Kinase === | === Dimerization of Anaplastic Lymphoma Kinase === | ||
After binding to one of its ligands, | 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" />. | ||
== Function == | == Function == | ||
ALK plays a role in [https://en.wikipedia.org/wiki/Cell_signaling cellular communication] and in the normal development and function of the [https://en.wikipedia.org/wiki/Nervous_system nervous system] It is present largely in the developing nervous system of a fetus and newborn, and overtime the expression of ALK dwindles with age. In addition to being expressed heavily in the brain, ALK has been shown to be present in the small intestine, testis, prostate, and colon <ref name="Della Corte">PMID:29455642</ref>. | |||
== Disease and Medical Relevance == | == Disease and Medical Relevance == | ||
=== Cancer === | === Cancer === | ||
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The regulation of ALK dimerization by ALKAL points to clear ways to inhibit ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. Studies have shown that approximately 70-80% of all patients who have Anaplastic Large Cell Lymphoma (ALCL) contain the genetic complex of the ALK gene and the nucleolar phosphoprotein B23, also called numatrin (NPM) gene translocation, creating the NPM-ALK complex. This chimeric protein is expressed from the NPM promoter, leading to the overexpression of the ALK catalytic domain. This overexpression of ALK is characteristic of most cancers that are linked to tyrosine kinases, as the overexpression of these proteins leads to uncontrollable growth <ref name="Della Corte">PMID:29455642</ref>. | The regulation of ALK dimerization by ALKAL points to clear ways to inhibit ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. Studies have shown that approximately 70-80% of all patients who have Anaplastic Large Cell Lymphoma (ALCL) contain the genetic complex of the ALK gene and the nucleolar phosphoprotein B23, also called numatrin (NPM) gene translocation, creating the NPM-ALK complex. This chimeric protein is expressed from the NPM promoter, leading to the overexpression of the ALK catalytic domain. This overexpression of ALK is characteristic of most cancers that are linked to tyrosine kinases, as the overexpression of these proteins leads to uncontrollable growth <ref name="Della Corte">PMID:29455642</ref>. | ||
==== Pediatric Neuroblastoma ==== | ==== Pediatric Neuroblastoma ==== | ||
Mutations in | Mutations in ALK can produce oncogenic activity and are a leading factor in the development of some pediatric neuroblastoma cases<ref name="Borenas" />. 8-10% of primary neuroblastoma patients are ALK positive<ref name="Borenas" /> suggesting that ALK overstimulation is a primary factor in propagating the growth of neuroblastoma. This overstimulation of ALK works in concert with the neural MYC oncogene, and uses the ALKAL2 ligand. Tyrosine kinase inhibitors are proposed to inhibit the growth of further neuroblastoma cells, creating a potential pathway of treatment<ref name="Borenas" /> | ||
</StructureSection>. | </StructureSection>. | ||
== References == | == References == | ||
<references/> | <references/> | ||