Anaplastic lymphoma kinase (ALK) extracellular ligand binding region 673-1025
要素
ALK tyrosine kinase receptor
キーワード
TRANSFERASE / Anaplastic lymphoma kinase / Receptor tyrosine kinases / RTK / FAM150 / LTK / DE NOVO PROTEIN
機能・相同性
機能・相同性情報
ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway ...ASP-3026-resistant ALK mutants / NVP-TAE684-resistant ALK mutants / alectinib-resistant ALK mutants / brigatinib-resistant ALK mutants / ceritinib-resistant ALK mutants / crizotinib-resistant ALK mutants / lorlatinib-resistant ALK mutants / MDK and PTN in ALK signaling / receptor signaling protein tyrosine kinase activator activity / regulation of dopamine receptor signaling pathway / response to environmental enrichment / ALK mutants bind TKIs / swimming behavior / positive regulation of dendrite development / regulation of neuron differentiation / Signaling by ALK / adult behavior / peptidyl-tyrosine autophosphorylation / neuron development / transmembrane receptor protein tyrosine kinase activity / negative regulation of lipid catabolic process / energy homeostasis / cell surface receptor protein tyrosine kinase signaling pathway / phosphorylation / hippocampus development / receptor protein-tyrosine kinase / Signaling by ALK fusions and activated point mutants / positive regulation of NF-kappaB transcription factor activity / heparin binding / regulation of cell population proliferation / protein tyrosine kinase activity / regulation of apoptotic process / protein autophosphorylation / receptor complex / signal transduction / protein-containing complex / extracellular exosome / ATP binding / identical protein binding / plasma membrane 類似検索 - 分子機能
Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / : ...Glycine rich protein / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Concanavalin A-like lectin/glucanase domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM122462
米国
引用
ジャーナル: Nature / 年: 2021 タイトル: Mechanism for the activation of the anaplastic lymphoma kinase receptor. 著者: Andrey V Reshetnyak / Paolo Rossi / Alexander G Myasnikov / Munia Sowaileh / Jyotidarsini Mohanty / Amanda Nourse / Darcie J Miller / Irit Lax / Joseph Schlessinger / Charalampos G Kalodimos / 要旨: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events ...Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.