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<scene name='90/904318/Alkal1membraneinteraction/2'>Text To Be Displayed</scene>{{Template:CH462_Biochemistry_II_2022}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | <scene name='90/904318/Alkal1membraneinteraction/2'>Text To Be Displayed</scene>{{Template:CH462_Biochemistry_II_2022}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
=Anaplastic Lymphoma Kinase= | =Anaplastic Lymphoma Kinase= | ||
==Background== | |||
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> | |||
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | ||
== Structure & Function == | |||
===Domains=== | |||
[[Image:2d_image.jpg|400 px|center|thumb|Fig.1 Anaplastic Lymphoma Kinase and its domains. The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK.]] | |||
The extracellular portion of ALK has an inactive state, which is its monomerized form, and an active dimerized state with its ligands bound. The monomer is shown to the right in Figure 1, which has many different domains. The growth factor-like domain (EGF) connects the extracellular domains to the transmembrane domain (cyan). The tumor necrosis factor-like domain (TNFL) has a beta-sandwich structure that provides important residues that act as the binding surface for the ligand (orange). The glycine-rich domain (GlyR) contains 14 rare polyglycine helices that are hydrogen-bound to each other (green). The <scene name='90/904318/Glycinerichdomain/1'>hexagonal orientation</scene> of these rare helices create a very rigid structure that is important for ALK function. The polyglycine extension loop (PXL) connects two of these polyglycine helices (pink). | |||
[[Image:Prote_ALK_Monomer_White.png|400 px|right|thumb|Figure 1: The ALK monomer unbound to ALKAL. Cyan: growth factor-like domain (EGF). Orange: tumor necrosis factor-like domain (TNFL). Green: glycine-rich domain (GlyR). Pink: polyglycine extension loop (PXL).]] | |||
The domains that aren't shown in Figure 1 but are shown in the domain map (Figure 2) that also make up the monomer are the heparin binding domains (HBDs), which 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) are 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. | |||
[[Image:Proteo_ALK-ALKAL_Monomer_White.png|400 px|right|thumb|Figure 2: ALK-ALKAL complex, showing the conformation change of ALK from the binding of ALKAL.]] | |||
===Conformational Change=== | |||
The anaplastic lymphoma kinase activating ligand (ALKAL) is a triple alpha-helix polypeptide structure that signals for a conformational change of ALK. It <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/3'>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. | |||
===Membrane Guidance of ALKAL to ALK=== | |||
The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged <scene name='90/904318/Alkalbindingsurfacewmembrane/1'>helix</scene> on ALKAL that faces the membrane. These <scene name='90/904318/Alkal1membraneinteraction/2'>residues that interact with the cell membrane</scene> guides ALKAL to ALK and correctly positions ALKAL for its <scene name='90/904318/Alk-alkal_binding_surface/4'>binding surface to face ALK's binding surface</scene>, which allows for a more favorable interaction. <ref>DOI: 10.1038/s41586-021-04140-8</ref> | |||
===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. | |||
==Disease== | |||
There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials. | |||
<scene name='90/904318/Premutationresidues/2'>mutated residues</scene> | |||
<scene name='90/904318/His694/2'>His694</scene> | |||
<scene name='90/904318/Phe856/1'>Phe856</scene> | |||
<scene name='90/904318/Arg753/2'>Arg753</scene> | |||
<scene name='90/904318/Gly747/1'>Gly747</scene> | |||
<ref>DOI: 10.1038/s41586-021-03959-5</ref> | |||
<ref>DOI: 10.1038/s41586-021-04141-7</ref> | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||