Title | Structure and function of the human apoptotic scramblase Xkr4. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Chakraborty S, Feng Z, Lee S, Alvarenga OE, Panda A, Zhang S, Bruni R, Khelashvili G, Gupta K, Accardi A |
Journal | Nat Commun |
Volume | 16 |
Issue | 1 |
Pagination | 7317 |
Date Published | 2025 Aug 08 |
ISSN | 2041-1723 |
Keywords | Apoptosis, 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. |
DOI | 10.1038/s41467-025-62739-1 |
Alternate Journal | Nat Commun |
PubMed ID | 40781244 |
PubMed Central ID | PMC12334663 |
Grant List | P41 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 |