Sandbox Reserved 1712: Difference between revisions

The anaplastic lymphoma kinase (ALK) was first discovered in 1994 as a tyrosine [https://en.wikipedia.org/wiki/Kinase kinase] in anaplastic large-cell lymphoma (ALCL) cells.<ref>DOI: 10.3390/ijms19113448</ref> The specific type of tyrosine kinase ALK is classified as is a [https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase] (RTK) and like other RTKs, it's an integral protein with extracellular and intracellular domains and is involved in transmembrane signaling and communication within the cell. ALK is commonly expressed in the development of the nervous system. Anaplastic lymphoma kinase receptor (ALKr) is the extracellular portion of the RTK that includes a binding surface for a ligand to bind. When the ALK activating ligand (ALKAL) binds to ALKr, this causes a conformational change of ALK, allowing two ALK-ALKAL complexes to interact with each other, which will then allow intracellular kinase domain of ALK to phosphorylate a tyrosine residue on a downstream enzyme, which will activate this enzyme and activate a signaling cascade. Abnormal forms of ALK are closely related to the formation of several cancers. <ref>DOI: 10.3390/ijms19113448</ref>

ALKr is in its inactive state as a <scene name='90/904317/Glycinerichmonomer/6'>monomer</scene> and has many different domains (Figure 1) that are important to the formation of the <scene name='90/904317/Dimer_full_colored/7'>dimerized</scene> active state, leading to ALK's main function. The tumor necrosis factor-like domian (TNFL), glycine-rich domain (GlyR), polyglycine extension loop (PXL), and growth factor-like domain (EGF) are the main domains of ALKr, and the only domains whose structures have been fully discovered are in color (Figure 1). The <scene name='90/904317/Glycinerichmonomer/11'>EGF</scene> (cyan) is the domain that binds to the TMH (transmembrane region), connecting the extracellular portion of ALK to the intracellular kinase domain.  <scene name='90/904317/Glycinerichmonomer/10'>TNFL</scene> (orange) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand. <scene name='90/904317/Glycinerichmonomer/8'>GlyR</scene> (green) contains 14 rare polyglycine helices that are hydrogen-bound to each other. The <scene name='90/904317/Glycinerichdomain/1'>hexagonal orientation</scene> of these rare helices create a rigid structure which allows it to function as a scaffold to anchor the ligand-binding site on the TNF-like domain while bound to the ligand. The <scene name='90/904317/Glycinerichmonomer/9'>PXL</scene> (pink) connects two of these polyglycine helices, and it also plays a role in forming important interactions of the dimerized activated state of ALKr.

The domains that aren't shown in Figure 2 but are shown in the domain map (Figure 1) also make up the monomer. The heparin binding domains (HBDs), are at the N-terminal end of the monomer. Heparin has been found to be a possible activating ligand of ALK.<ref>DOI: 10.1126/scisignal.2005916</ref> The transmembrane domain (TMH) contains the residues of ALK that are located within the membrane. The kinase domain is the intracellular portion of ALK that contains the Tyr residues which are auto-phosphorylated when ALK is activated, initiating a signaling cascade. <ref>DOI: 10.1038/s41586-021-04141-7</ref>

[[Image:Con chang 2D.png|600 px|center|thumb|Figure 3: ALK-ALKAL complex, showing the conformation change of ALK from the binding of ALKAL. [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]

The first step to the activation of ALK is to bind the ALK activating ligand (ALKAL) to ALKr. <scene name='90/904317/Monomerfullcolor/9'>ALKAL</scene> is a triple alpha-helix polypeptide structure that signals for a conformational change of ALK. What allows ALKAL to interact with ALKr is the cell membrane. The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904317/Monomerfullcolor/10'>alpha-helix</scene> on ALKAL that faces the membrane. These <scene name='90/904317/Alkal1membraneinteraction/5'>residues</scene> [https://www.rcsb.org/structure/7MZZ (7MZZ)] (Lys96, His99, Lys100) guide ALKAL to ALKr and correctly positions ALKAL for its binding surface to face ALKr's ligand site, which allows for a more favorable interaction.

ALKAL <scene name='90/904318/Dimer_full_colored/1'>binds</scene> to ALKr at the TNFL domain, which has important negatively charged residues that form <scene name='90/904318/Binding_surface_with_residues/3'>ionic bonds</scene> with positively charged residues on ALKAL. These bonds initiate the conformational change, as these residues can only come into close proximity with each other if the conformational change occurs. The PXL and GlyR domains hinge forward when the change is initiated<ref>DOI: 10.1038/s41586-021-04140-8</ref> (Figure 2). Glu978, Glu974, Glu859, and Tyr966 are the residues of ALKr that form these bonds with Arg123, Arg133, Arg136, Arg140, and Arg117 of ALKAL. Once the ALK-ALKAL complex is formed, the <scene name='90/904317/Dimer_full_colored/7'>dimerization</scene> of two ALK-ALKAL complexes occurs. The main driving force of the interaction between two ALK-ALKAL complexes that dimerize are hydrophobic interactions of the PXL loop of one ALKr with the other complex's ALKAL and TNFL domain of ALKr. This dimer of two ALK-ALKAL complexes is the active form of ALK, and it is now able to perform its main function of phosphorylation.

===Role of Activated ALK===

Once the ALKAL binds with ALK and dimerizes with another ALK-ALKAL complex, this activated conformation also initiates a conformational change of the intracellular kinase domain of ALK. This causes an autophosphorylation of several tyrosine residues of this domain, activating a signaling cascade with its kinase activity.

There are many <scene name='90/904317/Premutationresidues/1'>residues that could be mutated</scene> that would cause constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials (Figure 4). The <scene name='90/904317/His694/2'>His694</scene> that is mutated to arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK (Fig. 4a). The <scene name='90/904317/Gly747/1'>Gly747</scene> changing to arginine could cause possible oncogenic potentials which are not specified yet (Fig. 4b). The F856S and R753Q mutations are known to increase cytokine-dependent cell proliferation in certain cells. <ref>DOI:10.1038/s41586-021-03959-5</ref>

[[Image:Screen Shot 2022-04-13 at 5.30.04 PM.png|800 px|left|thumb|Figure 4: Mutated residues on ALK that contribute to stabilization of the active state of ALK, leading to many types of cancers. From left to right: F856S, G747R, H694R, R753Q [https://www.rcsb.org/structure/7N00 PDB: 7N00]]]