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bioRxiv · 10.1101/2022.09.08.506998

Cryo-EM analyses of wild-type and oncogenic KIT mutants reveal structural oncogenic plasticity and a novel Achilles heel for therapeutic intervention

Krimmer, S. G.·Bertoletti, N.·Suzuki, Y.·Katic, L.·Mohanty, J.·Shu, S.·Lee, S.·Lax, I.·Mi, W.·Schlessinger, J.
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Abstract

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.

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Krimmer, S. G., Bertoletti, N., Suzuki, Y., Katic, L., Mohanty, J., Shu, S., Lee, S., Lax, I., Mi, W., Schlessinger, J.. 2022-09-08. Cryo-EM analyses of wild-type and oncogenic KIT mutants reveal structural oncogenic plasticity and a novel Achilles heel for therapeutic intervention. https://doi.org/10.1101/2022.09.08.506998

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