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=== Known Extracellular Domains === | === Known Extracellular 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> | 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 ==== | ==== 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.<ref name="Reshetnyak" /> The GlyR domain also has a rare and unique structure of left-handed glycine helices with hexagonal hydrogen bonding | [[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 ==== | ==== 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" /> | 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 ==== | ==== 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 == | == Extracellular Domain Binding == | ||
=== Ligands === | === Ligands === | ||
The extracellular ligands of ALK are Anaplastic Lymphoma Kinase Ligand 2 (ALKAL 2) and Anaplastic Lymphoma Kinase Ligand 1 (ALKAL 1). | The extracellular ligands of ALK are Anaplastic Lymphoma Kinase Ligand 2 (ALKAL 2) and Anaplastic Lymphoma Kinase Ligand 1 (ALKAL 1). | ||
==== ALKAL2 ==== | ==== ALKAL2 ==== | ||
<scene name='90/904331/Alkal2/3'>ALKAL2</scene> is a ligand of ALK | <scene name='90/904331/Alkal2/3'>ALKAL2</scene> is a shared ligand of ALK and LTK. Full-length 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> and could potentially have therapeutic opportunities. | ||
==== ALKAL1 ==== | ==== ALKAL1 ==== | ||
<scene name='90/904331/Alkal1/5'>ALKAL1</scene> is a monomeric ligand of ALK | <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 === | === Binding Site === | ||
This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead | 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 === | === 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" />. | 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]<ref name ="Huang" /> ALK is present | 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]<ref name ="Huang" />. ALK is present in the developing nervous system of a fetus and newborn. ALK expression dwindles with age.<ref name ="Huang" /> In addition to being heavily expressed in the brain, ALK is 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 === | ||
In ALK [https://en.wikipedia.org/wiki/Fusion_protein fusion proteins], the ALK fusion partner may cause dimerization independent of ligand binding, | In ALK [https://en.wikipedia.org/wiki/Fusion_protein fusion proteins], the ALK fusion partner may cause dimerization independent of ligand binding, leading to oncogenic ALK activation <ref name="Huang" />. | ||
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. This complex is also called the numatrin (NPM) gene translocation and creates 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 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" /> | 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" />. | ||
== Inhibition and Regulation == | == Inhibition and Regulation == | ||
The regulation of ALK dimerization by ALKAL points to one clear way of inhibiting ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. As the dimerization of ALK is essential for activation of this protein, the inhibition of this activation is a potent way of inhibiting further ALK activity.<ref name ="Li" /> The inhibition and regulation of this extracellular region of ALK is actively being explored, as this part of ALK is part of what distinguishes it from other RTKs, like LTK. Researchers are currently exploring the use of [https://proteopedia.org/wiki/index.php/Antibody antibodies] and more specifically [https://proteopedia.org/wiki/index.php/Monoclonal_Antibody#:~:text=Monoclonal%20antibodies%20are%20immunoglobulins%20produced,pure%20homogeneous%20type%20of%20antibody. monoclonal antibodies]<ref name="Carpenter">PMID: 22266870</ref> as a means of inhibiting the activity of ALK through the extracellular domain. It is hypothesized that these monoclonal antibodies act by binding to the binding site of ALK, thus preventing ALKAL from binding<ref name="Li"/>, and thus induces cytotoxicity to the cancerous cell itself.<ref name ="Carpenter"/> | The regulation of ALK dimerization by ALKAL points to one clear way of inhibiting ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. As the dimerization of ALK is essential for activation of this protein, the inhibition of this activation is a potent way of inhibiting further ALK activity.<ref name ="Li" /> The inhibition and regulation of this extracellular region of ALK is actively being explored, as this part of ALK is part of what distinguishes it from other RTKs, like LTK. Researchers are currently exploring the use of [https://proteopedia.org/wiki/index.php/Antibody antibodies] and more specifically [https://proteopedia.org/wiki/index.php/Monoclonal_Antibody#:~:text=Monoclonal%20antibodies%20are%20immunoglobulins%20produced,pure%20homogeneous%20type%20of%20antibody. monoclonal antibodies]<ref name="Carpenter">PMID: 22266870</ref> as a means of inhibiting the activity of ALK through the extracellular domain. It is hypothesized that these monoclonal antibodies act by binding to the binding site of ALK, thus preventing ALKAL from binding<ref name="Li"/>, and thus induces cytotoxicity to the cancerous cell itself.<ref name ="Carpenter"/> | ||