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TitleCryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 120, Issue 13, Page e2300054120, Year 2023
Publish dateMar 28, 2023
AuthorsStefan G Krimmer / Nicole Bertoletti / Yoshihisa Suzuki / Luka Katic / Jyotidarsini Mohanty / Sheng Shu / Sangwon Lee / Irit Lax / Wei Mi / Joseph Schlessinger /
PubMed AbstractThe 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:36943885 / PubMed Central
MethodsEM (single particle)
Resolution3.17 - 13.1 Å
Structure data

27408

8dfm

EMDB-27408, PDB-8dfm:
Ectodomain of full-length wild-type KIT-SCF dimers
Method: EM (single particle) / Resolution: 3.45 Å

27410

8dfp

EMDB-27410, PDB-8dfp:
Ectodomain of full-length KIT(DupA502,Y503)-SCF dimers
Method: EM (single particle) / Resolution: 3.17 Å

27411

8dfq

EMDB-27411, PDB-8dfq:
Ectodomain of full-length KIT(T417I,delta418-419)-SCF dimers
Method: EM (single particle) / Resolution: 3.96 Å

EMDB-27495: Full-length KIT(T417I,delta418-419) dimers
Method: EM (single particle) / Resolution: 8.19 Å

EMDB-27496: Full-length KIT(T417I,delta418-419) dimers
Method: EM (single particle) / Resolution: 13.1 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / receptor tyrosine kinase / cell signaling / cancer / cryo-EM / KIT / stem cell factor / oncogenic mutant / extracellular domain / asymmetric interface / structural plasticity

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