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Structural basis for ligand reception by anaplastic lymphoma kinase.
Li, Tongqing; Stayrook, Steven E; Tsutsui, Yuko; Zhang, Jianan; Wang, Yueyue; Li, Hengyi; Proffitt, Andrew; Krimmer, Stefan G; Ahmed, Mansoor; Belliveau, Olivia; Walker, Ian X; Mudumbi, Krishna C; Suzuki, Yoshihisa; Lax, Irit; Alvarado, Diego; Lemmon, Mark A; Schlessinger, Joseph; Klein, Daryl E.
Afiliação
  • Li T; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Stayrook SE; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Tsutsui Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Zhang J; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Wang Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Li H; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Proffitt A; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Krimmer SG; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Ahmed M; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Belliveau O; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Walker IX; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Mudumbi KC; Celldex Therapeutics, New Haven, CT, USA.
  • Suzuki Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Lax I; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Alvarado D; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Lemmon MA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
  • Schlessinger J; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • Klein DE; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Nature ; 600(7887): 148-152, 2021 12.
Article em En | MEDLINE | ID: mdl-34819665
The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinase do Linfoma Anaplásico / Ligantes Limite: Animals / Humans / Infant / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinase do Linfoma Anaplásico / Ligantes Limite: Animals / Humans / Infant / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article