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bioRxiv · 10.1101/2021.04.28.441804

Structural basis of the P4B ATPase lipid flippase activity

Bai, L.·Jain, B. K.·You, Q.·Duan, H. D.·Graham, T. R.·Li, H.
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Abstract

P4 ATPases are lipid flippases that are phylogenetically grouped into P4A, P4B and P4C clades. The P4A ATPases are heterodimers composed of a catalytic -subunit and accessory {beta}-subunit, and the structures of several heterodimeric flippases have been reported. The S. cerevisiae Neo1 and its orthologs represent the P4B ATPases, which function as monomeric flippases without a {beta}-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the first structure of a P4B ATPase, Neo1, in its E1-ATP, E2P-transition, and E2P states. The structure reveals a conserved architecture as well as highly similar functional intermediate states relative to dimeric flippases. Consistently, structure-guided mutagenesis of residues in the proposed substrate translocation path disrupted Neo1s ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport.

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Bai, L., Jain, B. K., You, Q., Duan, H. D., Graham, T. R., Li, H.. 2021-04-28. Structural basis of the P4B ATPase lipid flippase activity. https://doi.org/10.1101/2021.04.28.441804

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