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| Title | Cryo-Structural Insights into Enzymatic Peptide Self-Assembly Driving Extrinsic Lytic Cell Death. |
|---|---|
| Journal, issue, pages | J Am Chem Soc, Vol. 148, Issue 13, Page 14117-14128, Year 2026 |
| Publish date | Apr 8, 2026 |
Authors | 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 / ![]() |
| PubMed Abstract | 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. |
External links | J Am Chem Soc / PubMed:41875418 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 2.5 - 2.8 Å |
| Structure data | EMDB-49891, PDB-9nwr: EMDB-49895, PDB-9nwv: EMDB-49913, PDB-9nxz: EMDB-49914, PDB-9ny0: |
| Source |
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Keywords | PROTEIN FIBRIL / D-peptide / peptide-fiber / helical |
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