Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic...

Area of Science:

• Oncology
• Molecular Biology
• Structural Biology

Background:

• The RET receptor tyrosine kinase is crucial for cell functions, and its dysregulation contributes to cancer development.
• Mutations in the RET extracellular domain (ECD) are linked to Multiple Endocrine Neoplasia type 2A (MEN2A), a hereditary cancer syndrome.
• Structural understanding of RET mutations in MEN2A remains limited.

Purpose of the Study:

• To elucidate the structural consequences of the C634R mutation in the RET ECD, the most prevalent MEN2A mutation.
• To investigate the impact of this mutation on RET dimerization and ligand binding.

Main Methods:

• Electron microscopy was employed to determine the structure of the RET C634R mutant ECD.
• Structural comparisons were made between the mutant and wild-type (WT) RET ECD in the presence and absence of ligands.

Main Results:

• The C634R mutation induces ligand-independent dimerization of the RET ECD in an unusual tail-to-tail conformation.
• This mutant dimer exhibits distinct structural characteristics compared to the ligand-induced dimer of WT RET.
• The RET C634R ECD dimer forms novel complexes with RET ligands, differing structurally from WT RET-ligand complexes.

Conclusions:

• The structural insights into the RET C634R mutant ECD reveal a potential mechanism for cancer induction in MEN2A, independent of ligand binding.
• These findings suggest that altered RET ECD structure and dimerization are key drivers of MEN2A pathogenesis.
• The study highlights potential therapeutic targets for intervening in RET-driven cancers.