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Research
2024.10.22

Substrate specificity controlled by the human P4-ATPases in neurological disorders (Nagata G, in PNAS)

PRESS RELEASE

ATP11A is a flippase that specifically translocates phosphatidylserine from the outer to the inner leaflet of plasma membranes. The research group of Shigekazu Nagata previously reported that a point mutation at its exoplasmic site causes the aberrant translocation of phosphatidylcholine (PtdCho), leading to the up-regulation of sphingomyelin (SM) synthetase and the accumulation of SM in the outer leaflet of the plasma membrane.  

In this thesis, the group identified three patients with a neuronal disorder, each carrying novel de novo point mutations near the substrate exit site of ATP11A. These mutations also resulted in the abnormal translocation of PtdCho to the intracellular region. Using Molecular Dynamics Simulation Analysis, they showed that these mutants bind PtdCho tightly at the exit gate, which may induce conformational changes at the entry gate, altering substrate specificity.
(online publication in Proc Natl Acad Sci U S A. on October 21, 2024) 


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Contact

Prof. Shigekazu Nagata

snagataifrec.osaka-u.ac.jp

Biochemistry & Immunology