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A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects
- Source :
- Biochemical Journal
- Publication Year :
- 2021
- Publisher :
- Portland Press Ltd., 2021.
-
Abstract
- NaCT (SLC13A5) is a Na+-coupled transporter for citrate, which is expressed in the liver, brain, testes, and bone. It is the mammalian homolog of Drosophila INDY, a cation-independent transporter for citrate, whose partial loss extends lifespan in the organism. In humans, loss-of-function mutations in NaCT cause a disease with severe neurological dysfunction, characterized by neonatal epilepsy and delayed brain development. In contrast with humans, deletion of NaCT in mice results in a beneficial metabolic phenotype with protection against diet-induced obesity and metabolic syndrome; the brain dysfunction is not readily noticeable. The disease-causing mutations are located in different regions of human NaCT protein, suggesting that different mutations might have different mechanisms for the loss of function. The beneficial effects of NaCT loss in the liver versus the detrimental effects of NaCT loss in the brain provide an opportunity to design high-affinity inhibitors for the transporter that do not cross the blood-brain barrier so that only the beneficial effects could be harnessed. To realize these goals, we need a detailed knowledge of the 3D structure of human NaCT. The recent report by Sauer et al. in Nature describing the cryo-EM structure of human NaCT represents such a milestone, paving the way for a better understanding of the structure-function relationship for this interesting and clinically important transporter.
- Subjects :
- Male
Aging
Brain development
homology modeling
disease-causing mutations
Disease
Biology
Biochemistry
Molecular Bases of Health & Disease
Citric Acid
03 medical and health sciences
Mice
0302 clinical medicine
Structural Biology
Partial loss
Commentaries
Animals
Humans
Homology modeling
Molecular Biology
EIEE-25
Loss function
030304 developmental biology
Diabetes & Metabolic Disorders
Dicarboxylic Acid Transporters
0303 health sciences
Symporters
Brain dysfunction
Cryoelectron Microscopy
Brain
Transporter
cryo-EM structure
Biological Transport
Cell Biology
structural impacts
Mutation
Cancer research
Metabolic phenotype
Cell Membranes, Excitation & Transport
NACT/SLC13A5
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 14708728 and 02646021
- Volume :
- 478
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....ca46401b52ff5901ebdbfdfe6807196b