Structure and function of the human apoptotic scramblase Xkr4.

TitleStructure and function of the human apoptotic scramblase Xkr4.
Publication TypeJournal Article
Year of Publication2025
AuthorsChakraborty S, Feng Z, Lee S, Alvarenga OE, Panda A, Zhang S, Bruni R, Khelashvili G, Gupta K, Accardi A
JournalNat Commun
Volume16
Issue1
Pagination7317
Date Published2025 Aug 08
ISSN2041-1723
KeywordsApoptosis, Cell Membrane, Cryoelectron Microscopy, Humans, Molecular Dynamics Simulation, Phosphatidylserines, Phospholipid Transfer Proteins, Protein Conformation
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.

DOI10.1038/s41467-025-62739-1
Alternate JournalNat Commun
PubMed ID40781244
PubMed Central IDPMC12334663
Grant ListP41 GM103310 / GM / NIGMS NIH HHS / United States
P41 GM116799 / GM / NIGMS NIH HHS / United States
1746886 / / NSF | Directorate for Biological Sciences (BIO) /
R01 AI178180 / AI / NIAID NIH HHS / United States
R01AI178180 / / Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID) /
R01GM141192 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
R01 GM141192 / GM / NIGMS NIH HHS / United States