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Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical
Anna Fassler Bakhman1, Michal Cohen2,3, Rachel Kolodny4
1Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa 3103301, Israel.
Abstract:
Variants in the human receptor tyrosine kinase RET can cause RET loss-of-function and Hirschsprung's disease (HSCR), while activating RET variants drive cancers including multiple endocrine neoplasia type 2 (MEN2). Paradoxically, some variants cause both HSCR and MEN2A. We curated 77 RET extracellular positions associated with HSCR, MEN2A or both and used a structure-based approach to predict the effects of variants at these positions on RET structure. Approximately 90% of HSCR-associated positions can, upon mutation, disrupt intramolecular interactions stabilizing RET tertiary structure via distinct mechanisms. Only a minority perturb protein-protein interactions needed for signal activation. In contrast, our analysis showed that ∼75% of variants causing MEN2A lead to an unpaired cysteine that can form an intermolecular disulfide bond between two RET monomers. Other MEN2A variants are likely to enhance RET homodimerization via membrane-proximal extracellular interactions. Substitutions that, concurrently, destabilize RET structure and result in an unpaired cysteine are predicted to cause the paradoxical co-occurrence of HSCR and MEN2A. Our findings lay out a mechanistic basis for almost all identified pathological RET mutations, and suggest therapeutic strategies for targeting RET activity in HSCR and MEN2A.
Insights
RET mutations cause Hirschsprung's disease (HSCR) or cancers like multiple endocrine neoplasia type 2 (MEN2). This study reveals how RET mutations disrupt structure, explaining HSCR and MEN2A, and guiding new therapies.
Area of Science:
- Molecular Biology
- Genetics
- Structural Biology
Background:
- Mutations in the human receptor tyrosine kinase RET gene are linked to developmental disorders and cancers.
- Loss-of-function RET mutations cause Hirschsprung's disease (HSCR), while activating mutations drive cancers like multiple endocrine neoplasia type 2 (MEN2).
- Some RET mutations paradoxically cause both HSCR and MEN2A, indicating complex molecular mechanisms.
Purpose of the Study:
- To elucidate the structural mechanisms underlying RET mutations associated with HSCR and MEN2A.
- To predict the impact of mutations at 77 specific RET extracellular positions on protein structure and function.
- To provide a mechanistic basis for RET-related diseases and inform therapeutic strategies.
Main Methods:
- Curated a dataset of 77 RET extracellular positions implicated in HSCR, MEN2A, or both.
- Employed a structure-based computational approach to predict mutation effects on RET tertiary structure.
- Analyzed alterations in intramolecular interactions, protein-protein interactions, and disulfide bond formation.
Main Results:
- Approximately 90% of HSCR-associated mutations disrupt intramolecular interactions stabilizing RET structure.
- A minority of HSCR mutations affect protein-protein interactions crucial for signal activation.
- Around 75% of MEN2A-associated mutations create unpaired cysteines, promoting intermolecular disulfide bonds and RET dimerization.
- Other MEN2A mutations enhance RET homodimerization through membrane-proximal extracellular interactions.
Conclusions:
- Structural destabilization underlies HSCR-associated RET mutations, while altered cysteine pairing drives MEN2A.
- Mutations causing both structural destabilization and unpaired cysteines explain the co-occurrence of HSCR and MEN2A.
- These findings offer a mechanistic framework for understanding pathological RET mutations and suggest potential therapeutic targets.
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