A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes
| Autor: | Makoto Suematsu, Kazuhiro Haginoya, Yuki Sugiura, Tomoyasu Noji, Shigeo Kure, Keita Hiraga, Kyoko Yamada, Yuki Ochiai, Fuminori Sugihara, Shigekazu Nagata, Yasuo Uchiyama, Takuo Nishimura, Hidetaka Kosako, Wataru Shoji, Chigure Suzuki, Atsuo Kikuchi, Masahito Ikawa, Hiroshi Ishikita, Yasuko Kobayashi, Katsumori Segawa, Kohei Nishino, Mitsuhiro Matsunaga, Shinya Iwasawa |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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