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Cryo-EM of Class-2 of YM1P nanotube
Structural highlights
Publication Abstract from PubMedProgrammed 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 A 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. Cryo-Structural Insights into Enzymatic Peptide Self-Assembly Driving Extrinsic Lytic Cell Death.,Yi M, Guo J, Zia A, Guo W, Tachiyama S, Ashton-Rickardt G, Tan W, Qiao Y, Gong Y, Egelman EH, Liu J, Wang F, Xu B J Am Chem Soc. 2026 Apr 8;148(13):14117-14128. doi: 10.1021/jacs.5c23283. Epub , 2026 Mar 24. PMID:41875418[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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