National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM138756
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
CA142746
米国
引用
ジャーナル: J Am Chem Soc / 年: 2026 タイトル: Cryo-Structural Insights into Enzymatic Peptide Self-Assembly Driving Extrinsic Lytic Cell Death. 著者: Meihui Yi / Jiaqi Guo / Ayisha Zia / Wangbiao Guo / Shoichi Tachiyama / Gabriel Ashton-Rickardt / Weiyi Tan / Yuchen Qiao / Yinan Gong / Edward H Egelman / Jun Liu / Fengbin Wang / Bing Xu / 要旨: Programmed lytic cell death, including pyroptosis and necroptosis, involves intracellular enzymes that form membrane-rupturing pores. Tumor-associated ectoenzymes such as alkaline phosphatase (ALP), ...Programmed lytic cell death, including pyroptosis and necroptosis, involves intracellular enzymes that form membrane-rupturing pores. Tumor-associated ectoenzymes such as alkaline phosphatase (ALP), however, offer the potential to initiate lytic death extrinsically. Here, we design a phospho-biphenyl-capped peptide precursor that is selectively dephosphorylated by ALP on cancer cell surfaces, triggering enzyme-instructed peptide self-assembly (EISA) into in situ peptide filaments. These supramolecular filaments physically breach the plasma membrane, overwhelm ESCRT-dependent membrane repair, and induce catastrophic calcium influx, cytoskeletal collapse, and organelle dysfunction. While cryo-EM uncovers 2.5-2.9 Å resolution details of ordered dimeric packing that underlies their mechanical rigidity and membrane-rupturing capability, cryo-electron tomography (cryo-ET) reveals the filament penetration of the plasma membrane in live cells. By reprogramming ALP from an immune checkpoint ectoenzyme into a pro-death catalyst, this work establishes a molecular mechanism linking enzymatic catalysis to supramolecular order and membrane failure. More broadly, it outlines a supramolecular chemical-biology framework in which enzyme-triggered assemblies function as programmable executors of cell death.