Summary
The human Na+/H+ exchanger 6 (HsNHE6) is crucial for regulating pH in recycling endosomes in the central nervous system. Mutations in HsNHE6 are linked to Christianson syndrome (CS), a severe neurodevelopmental disorder. However, the molecular mechanisms underlying HsNHE6 ion transport and its dysfunction due to CS mutations remain elusive. My research aims to bridge this knowledge gap by combining cellular and liposomal functional assays and single-particle cryo-electron microscopic structural investigations of HsNHE6. I will explore how dimerization in the lipid environment influences its ion transport mechanism, how the dimer functions as a whole, and how CS-associated mutations affect both dimerization and ion transport. I will conduct functional assays on heterodimeric HsNHE6, composed of wild-type (WT) and transport-deficient protomers, complemented by structural investigations to uncover the structure-function relationship during ion transport. I will identify HsNHE6-bound lipids and analyze HsNHE6 structure in its native environment utilizing detergent-free extraction. Furthermore, I will perform functional assessment in various lipid environments to unravel how the lipid environment influences dimerization and ion transport. Additionally, I aim to investigate whether and how CS-associated mutations lead to a loss-of-function phenotype and can exert a dominant-negative effect on a WT protomer by integrating functional assays with structural analyses of CS-mutant HsNHE6. The project aims to unravel the molecular mechanisms governing ion transport of HsNHE6 within the lipid bilayer and will provide insights into the molecular basis of CS. By integrating functional and structural data, it offers the potential to guide therapeutic targeting of HsNHE6 in the context of CS. The project is hosted at the Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, under the supervision of Assoc. Prof. Henriette E. Autzen.
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| Web resources: | https://cordis.europa.eu/project/id/101151923 |
| Start date: | 01-11-2024 |
| End date: | 31-10-2026 |
| Total budget - Public funding: | - 214 934,00 Euro |
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Original description
The human Na+/H+ exchanger 6 (HsNHE6) is crucial for regulating pH in recycling endosomes in the central nervous system. Mutations in HsNHE6 are linked to Christianson syndrome (CS), a severe neurodevelopmental disorder. However, the molecular mechanisms underlying HsNHE6 ion transport and its dysfunction due to CS mutations remain elusive. My research aims to bridge this knowledge gap by combining cellular and liposomal functional assays and single-particle cryo-electron microscopic structural investigations of HsNHE6. I will explore how dimerization in the lipid environment influences its ion transport mechanism, how the dimer functions as a whole, and how CS-associated mutations affect both dimerization and ion transport. I will conduct functional assays on heterodimeric HsNHE6, composed of wild-type (WT) and transport-deficient protomers, complemented by structural investigations to uncover the structure-function relationship during ion transport. I will identify HsNHE6-bound lipids and analyze HsNHE6 structure in its native environment utilizing detergent-free extraction. Furthermore, I will perform functional assessment in various lipid environments to unravel how the lipid environment influences dimerization and ion transport. Additionally, I aim to investigate whether and how CS-associated mutations lead to a loss-of-function phenotype and can exert a dominant-negative effect on a WT protomer by integrating functional assays with structural analyses of CS-mutant HsNHE6. The project aims to unravel the molecular mechanisms governing ion transport of HsNHE6 within the lipid bilayer and will provide insights into the molecular basis of CS. By integrating functional and structural data, it offers the potential to guide therapeutic targeting of HsNHE6 in the context of CS. The project is hosted at the Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, under the supervision of Assoc. Prof. Henriette E. Autzen.Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
03-10-2024
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