Cryo-EM structure of TMEM164 reveals distinct phospholipid remodeling mechanisms with anti-ferroptotic potential.

ABSTRACT: Phospholipids in cell membrane provide both regulatory and structural function of a cell. How lipid remodeling regulates cell fate remains less explored. Here we report the cryo-electron microscopy structure of TMEM164 identified by genome-wide CRISPR screen as an anti-ferroptotic factor. The overall architecture reveals a dimer of two 7 transmembrane domain monomers and a metal ion catalytic center with phospholipid substrate in a distinct polyunsaturated fatty acyl (PUFA)-C123 intermediate state. Both loss and gain of its function result in the decline of PUFA-ePE and elevation of C16/18:1-ePE, consequently confer resistance to GPX4 inhibitor RSL3 induced ferroptosis. Mutagenesis studies further validate critical residues for the catalytic center (C123) and the chelates center (E106, Y17

SUBMITTER: Ke M 

PROVIDER: S-EPMC12830759 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature