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Anaplastic Lymphoma Kinase

Background

The anaplastic lymphoma kinase (ALK) was first discovered in 1994 as a tyrosine kinase in anaplastic large-cell lymphoma (ALCL) cells.^[1] The specific type of tyrosine kinase ALK is classified as is a 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. ^[2]

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Structure & Function 1.1 Domains 1.2 Conformational Change 1.3 Membrane Guidance of ALKAL to ALK 1.4 Role of Activated ALK 2 Disease Structure & Function Domains 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 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). 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.[3] 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. 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) binds to the on the ALK at the TNFL domain. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward.[4] (Figure 2) ALK's TNFL has E978, E974, E859, and Y966 that form salt bridges with R123, R133, R136, R140, and R117 on ALKAL that allow for activation, leading to of two ALK-ALKAL monomers. Membrane Guidance of ALKAL to ALK The negatively charged phosphate groups on the cell membrane interact with a highly conserved positively charged on ALKAL that faces the membrane. These guides ALKAL to ALK and correctly positions ALKAL for its , which allows for a more favorable interaction. [5] 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. [6] [7]

References

1. ↑ Huang H. Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces. Int J Mol Sci. 2018 Nov 2;19(11). pii: ijms19113448. doi: 10.3390/ijms19113448. PMID:30400214 doi:http://dx.doi.org/10.3390/ijms19113448
2. ↑ Huang H. Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces. Int J Mol Sci. 2018 Nov 2;19(11). pii: ijms19113448. doi: 10.3390/ijms19113448. PMID:30400214 doi:http://dx.doi.org/10.3390/ijms19113448
3. ↑ Murray PB, Lax I, Reshetnyak A, Ligon GF, Lillquist JS, Natoli EJ Jr, Shi X, Folta-Stogniew E, Gunel M, Alvarado D, Schlessinger J. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci Signal. 2015 Jan 20;8(360):ra6. doi: 10.1126/scisignal.2005916. PMID:25605972 doi:http://dx.doi.org/10.1126/scisignal.2005916
4. ↑ Reshetnyak AV, Rossi P, Myasnikov AG, Sowaileh M, Mohanty J, Nourse A, Miller DJ, Lax I, Schlessinger J, Kalodimos CG. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature. 2021 Dec;600(7887):153-157. doi: 10.1038/s41586-021-04140-8. Epub 2021, Nov 24. PMID:34819673 doi:http://dx.doi.org/10.1038/s41586-021-04140-8
5. ↑ Reshetnyak AV, Rossi P, Myasnikov AG, Sowaileh M, Mohanty J, Nourse A, Miller DJ, Lax I, Schlessinger J, Kalodimos CG. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature. 2021 Dec;600(7887):153-157. doi: 10.1038/s41586-021-04140-8. Epub 2021, Nov 24. PMID:34819673 doi:http://dx.doi.org/10.1038/s41586-021-04140-8
6. ↑ De Munck S, Provost M, Kurikawa M, Omori I, Mukohyama J, Felix J, Bloch Y, Abdel-Wahab O, Bazan JF, Yoshimi A, Savvides SN. Structural basis of cytokine-mediated activation of ALK family receptors. Nature. 2021 Oct 13. pii: 10.1038/s41586-021-03959-5. doi:, 10.1038/s41586-021-03959-5. PMID:34646012 doi:http://dx.doi.org/10.1038/s41586-021-03959-5
7. ↑ Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature. 2021 Dec;600(7887):148-152. doi: 10.1038/s41586-021-04141-7. Epub 2021, Nov 24. PMID:34819665 doi:http://dx.doi.org/10.1038/s41586-021-04141-7