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TitleCryo-Structural Insights into Enzymatic Peptide Self-Assembly Driving Extrinsic Lytic Cell Death.
Journal, issue, pagesJ Am Chem Soc, Vol. 148, Issue 13, Page 14117-14128, Year 2026
Publish dateApr 8, 2026
AuthorsMeihui 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 AbstractProgrammed 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 linksJ Am Chem Soc / PubMed:41875418 / PubMed Central
MethodsEM (helical sym.)
Resolution2.5 - 2.8 Å
Structure data

EMDB-49891, PDB-9nwr:
Cryo-EM of Class-2 of YM1P nanotube
Method: EM (helical sym.) / Resolution: 2.8 Å

EMDB-49895, PDB-9nwv:
Cryo-EM of Class-3 of YM1P nanotube
Method: EM (helical sym.) / Resolution: 2.7 Å

EMDB-49913, PDB-9nxz:
Cryo-EM of Class-1 of YM1P nanotube
Method: EM (helical sym.) / Resolution: 2.8 Å

EMDB-49914, PDB-9ny0:
Cryo-EM of Class-4 of YM1P nanotube
Method: EM (helical sym.) / Resolution: 2.5 Å

Source
  • synthetic construct (others)
KeywordsPROTEIN FIBRIL / D-peptide / peptide-fiber / helical

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