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TitleMechanism for the activation of the anaplastic lymphoma kinase receptor.
Journal, issue, pagesNature, Vol. 600, Issue 7887, Page 153-157, Year 2021
Publish dateNov 24, 2021
AuthorsAndrey V Reshetnyak / Paolo Rossi / Alexander G Myasnikov / Munia Sowaileh / Jyotidarsini Mohanty / Amanda Nourse / Darcie J Miller / Irit Lax / Joseph Schlessinger / Charalampos G Kalodimos /
PubMed AbstractAnaplastic 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.
External linksNature / PubMed:34819673 / PubMed Central
MethodsEM (single particle) / NMR (solution) / X-ray diffraction
Resolution1.5 - 2.27 Å
Structure data

24095

7n00

EMDB-24095: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
PDB-7n00: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha
Method: EM (single particle) / Resolution: 2.27 Å

PDB-7mzw:
Anaplastic lymphoma kinase (ALK) extracellular ligand binding region 673-1025
Method: SOLUTION NMR

PDB-7mzx:
AUGalpha - FAM150B - ALKL2 77-152
Method: SOLUTION NMR

PDB-7mzy:
Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-986
Method: X-RAY DIFFRACTION / Resolution: 1.5 Å

PDB-7mzz:
AUGbeta - FAM150A - ALKL1 60-128
Method: SOLUTION NMR

Chemicals

ChemComp-ACT:
ACETATE ION

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Anaplastic lymphoma kinase / Receptor tyrosine kinases / RTK / FAM150 / LTK / DE NOVO PROTEIN / CYTOKINE / Anaplastic lymphoma kinase activating ligand / FAM150B / ALKL2 77-152 / Anaplastic lymphoma kinase (ALK) activating ligand

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