Structures of invertebrate PEZO-1 isoforms with a compact architecture and a dispensable pore-distal N-terminal blade.

PIEZO channels are mechanosensitive ion channels conserved from plants to humans, yet structures exist for only a few mammalian orthologs. We define the structural and functional diversity of Caenorhabditis elegans PEZO-1, a single gene with extensive alternative splicing, by determining cryo-electron microscopy structures of three representative isoforms: G (full length), K (lacking the pore-distal N-terminal blade), and L (missing most of the blade). PEZO-1G displays mechanically evoked currents yet adopts a compact, semi-flattened conformation that significantly differs from the mammalian domes. The blades exhibit a three-step slope architecture stabilized by inter-blade latching among transmembrane helical units, yielding a circular, steering-wheel-like arrangement. A wider cap enables distinct blade-cap contacts that stabilize a "toggle-down" conformation. Isoform K also exhibits mechanically evoked currents, indicating that the pore-distal N-terminal blade is dispensable for mechanoactivation. Computational membrane-deformation modeling indicates that the isoforms impose distinct curvatures on the bilayer. Our findings indicate an evolutionarily distinct architecture for PEZO-1.