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OCA, Jaime Prilusky, Elizabeth A. Palumbo, Elizabeth Sutherlin, R. Jeremy Johnson

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 <StructureSection load='7N00' size='350' side='right' caption=' Structure of Anaplastic Lymphoma Kinase [https://www.rcsb.org/structure/7N00 7N00]' scene='90/904331/Alk_full/1'>
 == Background ==
-Anaplastic Lymphoma Kinase (ALK) is a [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] receptor and a member of the family of [https://proteopedia.org/wiki/index.php/Receptor_tyrosine_kinases Receptor Tyrosine Kinases (RTKs)]<ref name="Iwahara">PMID:9053841</ref>. RTKs are a family of biomolecules that are primarily responsible for biosignaling pathways such as the insulin signaling pathway.<ref name="Huang" /> ALK was identified as a novel tyrosine phosphoprotein in 1994 in an analysis of [https://lymphoma.org/aboutlymphoma/nhl/alcl/ Anaplastic Large-Cell Lymphoma], the protein's namesake.<ref name ="Huang" /> A full analysis and characterization of ALK was completed in 1997, properly identifying it as an RTK, and linking it closely to [https://en.wikipedia.org/wiki/Leukocyte_receptor_tyrosine_kinase Leukocyte Tyrosine Kinase] (LTK).<ref name ="Huang" /> ALK's normal activity as a receptor tyrosine kinase is to transfer a gamma-phosphate group from adenosine triphosphate (ATP) to a tyrosine residue on its substrate.<ref name ="Huang" /> ALK is one of more than 50 RTKs encoded within the human genome, <ref name ="Huang" /> and its tyrosine kinase activity seems to be especially important in the developing nervous system. <ref name ="Huang" /> The ALK extracellular domain is becoming well characterized, as it is the primary binding site of ALK ligands that end up triggering the kinase activity, as ALK autophosphorylates itself.<ref name="Reshetnyak" /> There are four well-characterized domains on the ALK extracellular domain that are involved in binding the two main ligands of ALK that are discussed in this article.<ref name="Reshetnyak" /> ALK is most commonly associated with oncogenesis, as various factors, including overstimulation, lead to extreme cell proliferation.<ref name="Della Corte" /> It is primarily found in the fetal and infant developing nervous system, however when associated with cancer it can be found in systems other than the nervous system.<ref name="Carpenter" /> Examples of these include colon and prostate cancer, where ALK is not normally expressed.<ref name="Chen" /> This particular protein is interesting in part due to its unique structure, of that it shares the most similarity with LTKs and its association with devastating cancers.<ref name="DeMunck" />
+Anaplastic Lymphoma Kinase (ALK) is a [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] receptor and a member of the family of [https://proteopedia.org/wiki/index.php/Receptor_tyrosine_kinases Receptor Tyrosine Kinases (RTKs)]<ref name="Iwahara">PMID:9053841</ref>. RTKs are a family of biomolecules that are primarily responsible for biosignaling pathways such as the insulin signaling pathway.<ref name="Huang" /> ALK was identified as a novel tyrosine phosphoprotein in 1994 in an analysis of [https://lymphoma.org/aboutlymphoma/nhl/alcl/ Anaplastic Large-Cell Lymphoma], the protein's namesake.<ref name ="Huang" /> A full analysis and characterization of ALK was completed in 1997, properly identifying it as an RTK, and linking it closely to [https://en.wikipedia.org/wiki/Leukocyte_receptor_tyrosine_kinase Leukocyte Tyrosine Kinase] (LTK).<ref name ="Huang" /> ALK's normal activity as a receptor tyrosine kinase is to transfer a gamma-phosphate group from adenosine triphosphate (ATP) to a tyrosine residue on its substrate.<ref name ="Huang" /> ALK is one of more than 50 RTKs encoded within the human genome, <ref name ="Huang" /> and its tyrosine kinase activity seems to be especially important in the developing nervous system. <ref name ="Huang" /> The ALK extracellular domain is becoming well characterized, as it is the primary binding site of ALK ligands that end up triggering the kinase activity, as ALK autophosphorylates itself.<ref name="Reshetnyak" /> There are four well-characterized domains on the ALK extracellular domain that are involved in binding the two main ligands of ALK.<ref name="Reshetnyak" /> ALK is most commonly associated with oncogenesis, as various factors, including overstimulation, lead to extreme cell proliferation.<ref name="Della Corte" /> It is primarily found in the fetal and infant developing nervous system, however when associated with cancer it can be found in systems other than the nervous system.<ref name="Carpenter" /> Examples of these include colon and prostate cancer, where ALK is not normally expressed.<ref name="Chen" /> This particular protein is interesting in part due to its unique structure, of that it shares the most similarity with LTKs and its association with devastating cancers.<ref name="DeMunck" />
 == Structure ==
 ALK is a close homolog of LTK, and together these two homologs constitute a subgroup within the superfamily of [https://proteopedia.org/wiki/index.php/Insulin_receptor insulin receptors]<ref name="Della Corte" />. ALK is composed of three primary regions: the extracellular region, the transmembrane region, and the intracellular region.<ref name="Reshetnyak" /> [[Image:Full ALK Structure Graphic.PNG|600 px|right|thumb|Figure 1. Overview of Anaplastic Lymphoma Kinase Structure with domains where known structures are color coordinated and other domains are grayed out. The abbreviations are as follows: NTR-N-terminal Region, MAM-Meprin-A-5 protein-receptor protein tyrosine phosphatase μ, LDL-low-density lipoprotein receptor class A, THB-three helix bundle-like, GlyR-poly-glycine region, TNF-tumor necrosis factor-like domain, EGF-epidermal growth factor-like, TMH-transmembrane helix]] The extracellular region of ALK contains 8 total domains within 2 fragments.<ref name="Reshetnyak" /> A Three Helix Bundle-like domain (THB-like), a Poly-Glycine domain (GlyR), a Tumor Necrosis Factor-like domain (TNF-like), and an Epidermal Growth Factor-like domain (EGF-like) make up the ligand binding fragment while an N-terminal domain, two [https://en.wikipedia.org/wiki/Meprin_A meprin–A-5] protein–receptor protein tyrosine phosphatase μ (MAM) domains and a [https://en.wikipedia.org/wiki/Low-density_lipoprotein low-density lipoprotein] receptor class A (LDL) domain sandwiched between the two MAM domains make up the second fragment.<ref name="Reshetnyak" /> All four domains of the ligand binding fragment of the extracellular region contribute to ligand-binding <ref name ="Huang" />. The presence of an LDL domain sandwiched by two MAM domains is a unique feature that ALK does not share with other RTKs. The purpose behind this unique difference is still unclear, but the MAM region has been hypothesized to play a role in cell-cell signaling<ref name="Palmer">PMID:19459784</ref>. The [https://en.wikipedia.org/wiki/Transmembrane_domain transmembrane helical region] (TMH) bridges the gap between the intracellular and extracellular regions.<ref name="Reshetnyak" /> The intracellular tyrosine kinase region features the Kinase domain and the C-terminal end (Figure 1). <ref name="Reshetnyak" />