Sandbox Reserved 1705: Difference between revisions

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== General Structure ==

Anaplastic lymphoma kinase is a <scene name='90/904310/Dimer/2'>homodimer</scene>, each monomer consisting of seven domains and two regions <ref name="Tongqing">PMID:34819665</ref>. These domains and regions are as follows: N-terminal region (NTR), two meprin–A-5 protein–receptor protein tyrosine phosphatase μ domains (MAM), low density lipoprotein receptor class A domain (LDL), <scene name='90/904310/Tnf_highlighted_monomer/2'>tumor necrosis factor receptor-like domain</scene> (TNF), <scene name='90/904310/Glyr_highlighted_monomer/1'>glycine rich region</scene>(GlyR), <scene name='90/904310/Egf_highlighted_monomer/1'>epidermal growth factor receptor-like domain</scene> (EGF), transmembrane α-helix (TMH), kinase domain <ref name="Reshetnyak">PMID:34819673</ref>. The NTR functions as a signal peptide, the structure of which is yet to be determined. Though the biological roles and structures of MAM and LDL have not been determined, they are a very unique component to ALK. ALK is the only RTK that has two MAM domains and a LDL domain. Studies of other MAM domains have suggested that MAM may play a role in cell-cell interactions through homophilic binding <ref name="Huang">PMID: 30400214</ref>. The TNF-like domain assists in mediating mature T-cell receptor induced apoptosis. ~~The glycine rich region is a part of~~ the TNF domain. The GlyR region consists of multiple glycine helices which is a highly unique structure. Though the function of ALK's EGF domain is unknown, we do know that all EGF domains are found in the extracellular region and are thought to be important building blocks for extracellular proteins <ref name="Hallberg">PMID:24060861</ref>. The TMH connects the extracellular and intracellular regions of ALK through the plasma membrane. The kinase domain is in the intracellular region and is phosphorylated at positions Y1278, Y1282, and Y1283 through the tyrosine phosphorylation mechanism in order to begin signaling cascades <ref name="Selander-Sunnerhagen">PMID:1527084</ref>. The structures of the N-terminal region, MAM, and LDL have not been determined. Only the TNF, GlyR, and EGF portions of ALK are required for ligand binding. All portions of anaplastic lymphoma kinase are located in the extracellular domain except for the transmembrane α-helix which is in the transmembrane region and the kinase domain that is located in the intracellular region.

Anaplastic lymphoma kinase is a <scene name='90/904310/Dimer/2'>homodimer</scene>, each monomer consisting of seven domains and two regions <ref name="Tongqing">PMID:34819665</ref>. These domains and regions are as follows: N-terminal region (NTR), two meprin–A-5 protein–receptor protein tyrosine phosphatase μ domains (MAM), low density lipoprotein receptor class A domain (LDL), <scene name='90/904310/Tnf_highlighted_monomer/2'>tumor necrosis factor receptor-like domain</scene> (TNF), <scene name='90/904310/Glyr_highlighted_monomer/1'>glycine rich region</scene>(GlyR), <scene name='90/904310/Egf_highlighted_monomer/1'>epidermal growth factor receptor-like domain</scene> (EGF), transmembrane α-helix (TMH), kinase domain <ref name="Reshetnyak">PMID:34819673</ref>. The NTR functions as a signal peptide, the structure of which is yet to be determined. Though the biological roles and structures of MAM and LDL have not been determined, they are a very unique component to ALK. ALK is the only RTK that has two MAM domains and a LDL domain. Studies of other MAM domains have suggested that MAM may play a role in cell-cell interactions through homophilic binding <ref name="Huang">PMID: 30400214</ref>. The TNF-like domain assists in mediating mature T-cell receptor induced apoptosis. Both the TNF domain and GlyR region are discontinuous, traversing each other frequently <ref name="Reshetnyak">PMID:34819673</ref>. The GlyR region consists of multiple glycine helices which is a highly unique structure. Though the function of ALK's EGF domain is unknown, we do know that all EGF domains are found in the extracellular region and are thought to be important building blocks for extracellular proteins <ref name="Hallberg">PMID:24060861</ref>. The TMH connects the extracellular and intracellular regions of ALK through the plasma membrane. The kinase domain is in the intracellular region and is phosphorylated at positions Y1278, Y1282, and Y1283 through the tyrosine phosphorylation mechanism in order to begin signaling cascades <ref name="Selander-Sunnerhagen">PMID:1527084</ref>. The structures of the N-terminal region, MAM, and LDL have not been determined. Only the TNF, GlyR, and EGF portions of ALK are required for ligand binding. All portions of anaplastic lymphoma kinase are located in the extracellular domain except for the transmembrane α-helix which is in the transmembrane region and the kinase domain that is located in the intracellular region.

=== Ligand Binding===

The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and <scene name='90/904310/Ligand/1'>AUG</scene> in a dimeric fashion. It's biologically preferred ligand is AUG, a 128 monomer peptide ligand. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 2). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/3'>bound</scene> (Step 2, Figure 2), ALK undergoes a conformational change and folds over so that the positively charged residues on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane (Step 3, Figure 2). The residues of ALK and it's ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/4'>salt bridges</scene>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer. [[Image:ALK Conformational Change Gif.gif|850 px|left|thumb|Figure 2: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]

[[Image:ALK Conformational Change Gif.gif|850 px|left|thumb|Figure 2: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]

The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and <scene name='90/904310/Ligand/1'>AUG</scene> in a dimeric fashion. It's biologically preferred ligand is AUG, a 128 monomer peptide ligand. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 2). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/3'>bound</scene> (Step 2, Figure 2), ALK undergoes a conformational change and folds over so that the positively charged residues on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane (Step 3, Figure 2). The residues of ALK and it's ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/4'>salt bridges</scene>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer.

==== Tyrosine Phosphorylation Mechanism ====

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 == General Structure ==
-Anaplastic lymphoma kinase is a <scene name='90/904310/Dimer/2'>homodimer</scene>, each monomer consisting of seven domains and two regions <ref name="Tongqing">PMID:34819665</ref>. These domains and regions are as follows: N-terminal region (NTR), two meprin–A-5 protein–receptor protein tyrosine phosphatase μ domains (MAM), low density lipoprotein receptor class A domain (LDL), <scene name='90/904310/Tnf_highlighted_monomer/2'>tumor necrosis factor receptor-like domain</scene> (TNF), <scene name='90/904310/Glyr_highlighted_monomer/1'>glycine rich region</scene>(GlyR), <scene name='90/904310/Egf_highlighted_monomer/1'>epidermal growth factor receptor-like domain</scene> (EGF), transmembrane α-helix (TMH), kinase domain <ref name="Reshetnyak">PMID:34819673</ref>. The NTR functions as a signal peptide, the structure of which is yet to be determined. Though the biological roles and structures of MAM and LDL have not been determined, they are a very unique component to ALK. ALK is the only RTK that has two MAM domains and a LDL domain. Studies of other MAM domains have suggested that MAM may play a role in cell-cell interactions through homophilic binding <ref name="Huang">PMID: 30400214</ref>. The TNF-like domain assists in mediating mature T-cell receptor induced apoptosis. The glycine rich region is a part of the TNF domain. The GlyR region consists of multiple glycine helices which is a highly unique structure. Though the function of ALK's EGF domain is unknown, we do know that all EGF domains are found in the extracellular region and are thought to be important building blocks for extracellular proteins <ref name="Hallberg">PMID:24060861</ref>. The TMH connects the extracellular and intracellular regions of ALK through the plasma membrane. The kinase domain is in the intracellular region and is phosphorylated at positions Y1278, Y1282, and Y1283 through the tyrosine phosphorylation mechanism in order to begin signaling cascades <ref name="Selander-Sunnerhagen">PMID:1527084</ref>. The structures of the N-terminal region, MAM, and LDL have not been determined.  Only the TNF, GlyR, and EGF portions of ALK are required for ligand binding. All portions of anaplastic lymphoma kinase are located in the extracellular domain except for the transmembrane α-helix which is in the transmembrane region and the kinase domain that is located in the intracellular region.
+Anaplastic lymphoma kinase is a <scene name='90/904310/Dimer/2'>homodimer</scene>, each monomer consisting of seven domains and two regions <ref name="Tongqing">PMID:34819665</ref>. These domains and regions are as follows: N-terminal region (NTR), two meprin–A-5 protein–receptor protein tyrosine phosphatase μ domains (MAM), low density lipoprotein receptor class A domain (LDL), <scene name='90/904310/Tnf_highlighted_monomer/2'>tumor necrosis factor receptor-like domain</scene> (TNF), <scene name='90/904310/Glyr_highlighted_monomer/1'>glycine rich region</scene>(GlyR), <scene name='90/904310/Egf_highlighted_monomer/1'>epidermal growth factor receptor-like domain</scene> (EGF), transmembrane α-helix (TMH), kinase domain <ref name="Reshetnyak">PMID:34819673</ref>. The NTR functions as a signal peptide, the structure of which is yet to be determined. Though the biological roles and structures of MAM and LDL have not been determined, they are a very unique component to ALK. ALK is the only RTK that has two MAM domains and a LDL domain. Studies of other MAM domains have suggested that MAM may play a role in cell-cell interactions through homophilic binding <ref name="Huang">PMID: 30400214</ref>. The TNF-like domain assists in mediating mature T-cell receptor induced apoptosis. Both the TNF domain and GlyR region are discontinuous, traversing each other frequently <ref name="Reshetnyak">PMID:34819673</ref>. The GlyR region consists of multiple glycine helices which is a highly unique structure. Though the function of ALK's EGF domain is unknown, we do know that all EGF domains are found in the extracellular region and are thought to be important building blocks for extracellular proteins <ref name="Hallberg">PMID:24060861</ref>. The TMH connects the extracellular and intracellular regions of ALK through the plasma membrane. The kinase domain is in the intracellular region and is phosphorylated at positions Y1278, Y1282, and Y1283 through the tyrosine phosphorylation mechanism in order to begin signaling cascades <ref name="Selander-Sunnerhagen">PMID:1527084</ref>. The structures of the N-terminal region, MAM, and LDL have not been determined.  Only the TNF, GlyR, and EGF portions of ALK are required for ligand binding. All portions of anaplastic lymphoma kinase are located in the extracellular domain except for the transmembrane α-helix which is in the transmembrane region and the kinase domain that is located in the intracellular region.
 === Ligand Binding===
-The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and <scene name='90/904310/Ligand/1'>AUG</scene> in a dimeric fashion. It's biologically preferred ligand is AUG, a 128 monomer peptide ligand. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 2). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/3'>bound</scene> (Step 2, Figure 2), ALK undergoes a conformational change and folds over so that the positively charged residues on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane (Step 3, Figure 2). The residues of ALK and it's ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/4'>salt bridges</scene>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer. [[Image:ALK Conformational Change Gif.gif|850 px|left|thumb|Figure 2: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]
+ [[Image:ALK Conformational Change Gif.gif|850 px|left|thumb|Figure 2: Gif-image of the conformational change occurring in the extracellular region of Anaplastic Lymphoma Kinase once the AUG ligand has bound to the ligand binding site. This change is stabilized through contacts of the AUG and the plasma membrane. The video was made using stop motion animation techniques, then converted to gif format using EZgif.]]
+The ligands recognized by anaplastic lymphoma kinase are FAM150 in a monomeric fashion and <scene name='90/904310/Ligand/1'>AUG</scene> in a dimeric fashion. It's biologically preferred ligand is AUG, a 128 monomer peptide ligand. The binding of ALK to it's ligand results in homodimerization and a conformational change. Prior to the ligand binding to anaplastic lymphoma kinase, the extracellular domain is oriented vertically and perpendicularly to the plasma membrane (Step 1, Figure 2). Once the ligand is <scene name='90/904310/Dimer_ligand_complex/3'>bound</scene> (Step 2, Figure 2), ALK undergoes a conformational change and folds over so that the positively charged residues on the portion of the protein previously oriented vertically is now interacting with the negatively charged residues on the plasma membrane (Step 3, Figure 2). The residues of ALK and it's ligand interact through the formation of <scene name='90/904310/Dimer-ligand-interface/4'>salt bridges</scene>. It has been hypothesized that the GlyR region plays a role in the flexibility needed to complete the conformational change. This conformational change via ligand binding induces the auto-activation of the kinase domain, in which the domains use the tyrosine phosphorylation mechanism to phosphorylate tyrosine residues on the opposite monomer.
 ==== Tyrosine Phosphorylation Mechanism ====