Cryo-EM analyses of wild-type and oncogenic KIT mutants reveal structural oncogenic plasticity and a novel “Achilles heel” for therapeutic intervention
biorxiv(2022)
摘要
The receptor tyrosine kinase KIT and its ligand 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 and mast cell leukemia, are driven by somatic gain-of-function KIT mutations. Here, we report cryo-EM structural analyses of full-length wild-type and two oncogenic KIT mutants, which show that the symmetric arrangement of ligand-occupied KIT dimers is converted into 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. SCF binding to this mutant fully restores the conformation of wild-type KIT dimers, revealing an unexpected structural plasticity of oncogenic mutants that may offer new therapeutic modality.
### Competing Interest Statement
The authors have declared no competing interest.
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关键词
oncogenic kit mutants,structural oncogenic plasticity,wild-type
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