| Autor: |
Krimmer SG; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Bertoletti N; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Suzuki Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Katic L; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Mohanty J; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Shu S; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Lee S; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Lax I; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Mi W; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520., Schlessinger J; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520. |
| Abstrakt: |
The receptor tyrosine kinase KIT and its ligand stem cell factor (SCF) are required for the development of hematopoietic stem cells, germ cells, and other cells. A variety of human cancers, such as acute myeloid leukemia, gastrointestinal stromal tumor, and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo electron microscopy (cryo-EM) structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the overall symmetric arrangement of the extracellular domain of ligand-occupied KIT dimers contains asymmetric D5 homotypic contacts juxtaposing the plasma membrane. Mutational analysis of KIT reveals in D5 region an "Achilles heel" for therapeutic intervention. A ligand-sensitized oncogenic KIT mutant exhibits a more comprehensive and stable D5 asymmetric conformation. A constitutively active ligand-independent oncogenic KIT mutant adopts a V-shaped conformation solely held by D5-mediated contacts. Binding of SCF to this mutant fully restores the conformation of wild-type KIT dimers, including the formation of salt bridges responsible for D4 homotypic contacts and other hallmarks of SCF-induced KIT dimerization. These experiments reveal an unexpected structural plasticity of oncogenic KIT mutants and a therapeutic target in D5. |
