Activation and substrate specificity of the human P4-ATPase ATP8B1

Thibaud Dieudonné (), Felix Kümmerer, Michelle Juknaviciute Laursen, Charlott Stock, Rasmus Kock Flygaard, Syma Khalid, Guillaume Lenoir, Joseph A. Lyons, Kresten Lindorff-Larsen and Poul Nissen ()
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Thibaud Dieudonné: Aarhus University
Felix Kümmerer: University of Copenhagen
Michelle Juknaviciute Laursen: Aarhus University
Charlott Stock: Aarhus University
Rasmus Kock Flygaard: Aarhus University
Syma Khalid: University of Oxford
Guillaume Lenoir: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Joseph A. Lyons: Aarhus University
Kresten Lindorff-Larsen: University of Copenhagen
Poul Nissen: Aarhus University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 Å overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P3 binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of a broad lipid specificity of ATP8B1 and adds phosphatidylinositol as a transport substrate for ATP8B1. We report a critical role of the sn-2 ester bond of glycerophospholipids in substrate recognition by ATP8B1 through conserved S403. These findings provide fundamental insights into ATP8B1 catalytic cycle and regulation, and substrate recognition in P4-ATPases.

Date: 2023
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DOI: 10.1038/s41467-023-42828-9

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