Structural and Mechanistic Insights Into GSDME Pore Formation and Functional Regulation

Cryo-EM structures of gasdermin E pores, with oligomeric stoichiometries ranging from 23 to 29 protomers, expose how pore assembly works. Mutagenesis, liposome leakage assays and cancer-associated mutation analysis identified residues governing membrane binding, shallow membrane insertion and oligomerization via three interfaces, while molecular dynamics simulations showed anionic TMCL2 recruited by basic residues to aid membrane penetration. The work supports a stepwise, time-dependent mechanism of GSDME pore assembly.