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| Title | Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A. |
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| Journal, issue, pages | J Biol Chem, Vol. 298, Issue 10, Page 102380, Year 2022 |
| Publish date | Aug 17, 2022 |
 Authors | Yixin Liu / Orquidea De Castro Ribeiro / Outi Haapanen / Gregory B Craven / Vivek Sharma / Stephen P Muench / Adrian Goldman /   |
| PubMed Abstract | The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. ...The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RET ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention. |
 External links | J Biol Chem / PubMed:35985422 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 8.0 - 22.0 Å |
| Structure data |  EMDB-13421: Cryo-EM maps of the RET/GDF15/GFRAL complex  EMDB-13688: Negative stain EM map of the extracellular domain of the RET(C634R) mutant dimer  EMDB-13689: Negative stain EM map of the extracellular domain of the RET(C634R)/GDF15/GFRAL complex |
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Homo sapiens (human)