RRC ID 77503
Author Segawa K, Kikuchi A, Noji T, Sugiura Y, Hiraga K, Suzuki C, Haginoya K, Kobayashi Y, Matsunaga M, Ochiai Y, Yamada K, Nishimura T, Iwasawa S, Shoji W, Sugihara F, Nishino K, Kosako H, Ikawa M, Uchiyama Y, Suematsu M, Ishikita H, Kure S, Nagata S.
Title A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes.
Journal J Clin Invest
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.
Volume 131(18)
Published 2021-9-15
DOI 10.1172/JCI148005
PII e148005
PMID 34403372
PMC PMC8439608
MeSH ATP Binding Cassette Transporter 1 / deficiency ATP Binding Cassette Transporter 1 / genetics* ATP Binding Cassette Transporter 1 / metabolism ATP-Binding Cassette Transporters / chemistry ATP-Binding Cassette Transporters / genetics* ATP-Binding Cassette Transporters / metabolism* Adult Amino Acid Sequence Amino Acid Substitution Animals Brain / diagnostic imaging Cell Membrane / metabolism Female Genes, Lethal Heterozygote Humans Male Membrane Lipids / metabolism Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Mutant Strains Molecular Dynamics Simulation Neurodegenerative Diseases / diagnostic imaging Neurodegenerative Diseases / genetics* Neurodegenerative Diseases / metabolism* Phosphatidylcholines / metabolism* Phospholipid Transfer Proteins / genetics Phospholipid Transfer Proteins / metabolism Point Mutation* Pregnancy
IF 11.864
Human and Animal Cells ASF-4-3L(RCB3580)