[YSA] Young Scientist Award Symposium

[YSA-3(2P-21)] Cryo-EM structures of ATP13A2 reveal transport mechanism of polyamines

^○Atsuhiro Tomita¹, Takashi Daiho², Tomohiro Nishizawa¹, Osamu Nureki¹ (1.Dept. of Biol. Sci., Univ. of Tokyo, 2.Dept. of Med., Asahikawa Medical Univ.)

Polyamines are essential organic compounds for maintaining various biological activities in all eukaryotes. Among polyamines, spermine (SPM) plays especially important roles in cells, such as the regulation of transcriptional activity and protection of cells from damage caused by reactive oxygen species (ROS). Type VB P-type ATPase (P5B-ATPase) ATP13A2 was identified as the lysosomal polyamine exporter that plays a crucial role in the SPM uptake into the cytoplasm. Several mutations in ATP13A2 are also associated with Parkinson's disease. While the mechanisms for the ion-pumping and phospholipid-flippase members of the P-type ATPase family have been well examined, the polyamine transport mechanism by ATP13A2 is still elusive.Here, we report the cryo-electron microscopy (cryo-EM) structures of the human ATP13A2 in its four distinct intermediates: E1-ATP, E1P-ADP, E2P, and E2Pi states. These structures, together with biochemical and computational analyses, have revealed the unique mechanism for the recognition and transport of polyamines by ATP13A2.