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== Structure == | == Structure == | ||
ALK is a close homolog of LTK, and together these two homologues constitute a subgroup within the superfamily of [https://proteopedia.org/wiki/index.php/Insulin_receptor insulin receptors] (IR). ALK is composed of three primary regions: the extracellular region, the transmembrane region, and the intracellular region. [[Image:Full ALK Structure Graphic.PNG|600 px|right|thumb|Figure 1. Overview of Anaplastic Lymphoma Kinase Structure with domains where known structure are color coordinated and other domains are grayed out.]] The extracellular region of ALK contains 8 total domains within 2 fragments. 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 a 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. 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. The [https://en.wikipedia.org/wiki/Transmembrane_domain transmembrane helical region] (TMH) bridges the gap between the intracellular and extracellular regions. The intracellular tyrosine kinase domain features the Kinase domain and the C-terminal end (Figure 1). | ALK is a close homolog of LTK, and together these two homologues constitute a subgroup within the superfamily of [https://proteopedia.org/wiki/index.php/Insulin_receptor insulin receptors] (IR). ALK is composed of three primary regions: the extracellular region, the transmembrane region, and the intracellular region. [[Image:Full ALK Structure Graphic.PNG|600 px|right|thumb|Figure 1. Overview of Anaplastic Lymphoma Kinase Structure with domains where known structure are color coordinated and other domains are grayed out.]] The extracellular region of ALK contains 8 total domains within 2 fragments. 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 a 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. 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. The [https://en.wikipedia.org/wiki/Transmembrane_domain transmembrane helical region] (TMH) bridges the gap between the intracellular and extracellular regions. The intracellular tyrosine kinase domain features the Kinase domain and the C-terminal end (Figure 1). | ||
=== Extracellular Domains === | === Known Extracellular Domains === | ||
==== Three Helix Bundle-like Domain ==== | ==== Three Helix Bundle-like Domain ==== | ||
The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function as it interacts with the TNF-like domain upon ligand binding.<ref name="Reshetnyak" /> The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain.<ref name="Reshetnyak" /> This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding.<ref name="Reshetnyak" /> The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" /> | The <scene name='90/904332/Thb-like_domain/1'>Three Helix Bundle-like Domain</scene> mainly has a structural function as it interacts with the TNF-like domain upon ligand binding.<ref name="Reshetnyak" /> The THB-like domain's α-helix interacts with the helix α-1' and β strand A-1' on the TNF-like domain.<ref name="Reshetnyak" /> This outermost region of the extracellular ligand-binding domain undergoes rigorous structural reorientation upon ligand binding.<ref name="Reshetnyak" /> The THB-like is primarily involved in the dimerization motif of ALK, which dimerizes upon ligand binding. <ref name="Reshetnyak" /> | ||