Structural basis of the P4B ATPase lipid flippase activity

Lin Bai (), Bhawik K. Jain, Qinglong You, H. Diessel Duan, Mehmet Takar, Todd R. Graham () and Huilin Li ()
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Lin Bai: Peking University
Bhawik K. Jain: Vanderbilt University
Qinglong You: Van Andel Institute
H. Diessel Duan: Van Andel Institute
Mehmet Takar: Vanderbilt University
Todd R. Graham: Vanderbilt University
Huilin Li: Van Andel Institute

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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 α-subunit and accessory β-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 β-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the 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 Neo1’s ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport.

Date: 2021
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DOI: 10.1038/s41467-021-26273-0

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