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A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes
- Source :
- J Clin Invest
- Publication Year :
- 2021
-
Abstract
- ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.
- Subjects :
- Adult
Male
Heterozygote
Mutant
Molecular Dynamics Simulation
medicine.disease_cause
chemistry.chemical_compound
Membrane Lipids
Mice
Pregnancy
Phosphatidylcholine
medicine
Animals
Humans
Point Mutation
Amino Acid Sequence
Phospholipid Transfer Proteins
Mutation
Mice, Inbred ICR
Cell growth
Point mutation
Cell Membrane
Brain
Neurodegenerative Diseases
General Medicine
Phosphatidylserine
Mice, Mutant Strains
Cell biology
Mice, Inbred C57BL
Transmembrane domain
chemistry
Amino Acid Substitution
Phosphatidylcholines
lipids (amino acids, peptides, and proteins)
ATP-Binding Cassette Transporters
Female
Genes, Lethal
Sphingomyelin
ATP Binding Cassette Transporter 1
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 131
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....98d9500bf41887fe56bf82f95617abaf