Structure and function of the human apoptotic scramblase Xkr4

Sayan Chakraborty, Zhang Feng, Sangyun Lee, Omar E. Alvarenga, Aniruddha Panda, Shuming Zhang, Renato Bruni, George Khelashvili, Kallol Gupta and Alessio Accardi ()
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Sayan Chakraborty: Weill Cornell Medical College
Zhang Feng: Weill Cornell Medical College
Sangyun Lee: Weill Cornell Medical College
Omar E. Alvarenga: Weill Cornell Medical College
Aniruddha Panda: Yale University
Shuming Zhang: Weill Cornell Medical College
Renato Bruni: New York Structural Biology Center
George Khelashvili: Weill Cornell Medical College
Kallol Gupta: Yale University
Alessio Accardi: Weill Cornell Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Phosphatidylserine externalization on the surface of dying cells is a key signal for their recognition and clearance by macrophages and is mediated by members of the X-Kell related (Xkr) protein family. Defective Xkr-mediated scrambling impairs clearance, leading to inflammation. It was proposed that activation of the Xkr4 apoptotic scramblase requires caspase cleavage, followed by dimerization and ligand binding. Here, using a combination of biochemical approaches we show that purified monomeric, full-length human Xkr4 (hXkr4) scrambles lipids. CryoEM imaging shows that hXkr4 adopts a novel conformation, where three conserved acidic residues create a negative electrostatic surface embedded in the membrane. Molecular dynamics simulations show this conformation induces membrane thinning, which could promote scrambling. Thinning is ablated or reduced in conditions where scrambling is abolished or reduced. Our work provides insights into the molecular mechanisms of hXkr4 scrambling and suggests the ability to thin membranes might be a general property of active scramblases.

Date: 2025
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DOI: 10.1038/s41467-025-62739-1

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