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

## TL;DR

The study reveals that nematode PEZO-1 ion channels have a unique compact structure and can function without a specific part of the protein, suggesting evolutionary differences in how these channels work.

## Contribution

The paper presents novel cryo-EM structures of C. elegans PEZO-1 isoforms and shows the N-terminal blade is not essential for mechanosensation.

## Key findings

- PEZO-1G adopts a compact, semi-flattened conformation distinct from mammalian PIEZOs.
- The pore-distal N-terminal blade is dispensable for mechanosensation in isoform K.
- Different PEZO-1 isoforms impose distinct membrane curvatures, indicating evolutionary divergence.

## Abstract

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.

Bell et al. show that nematode PEZO-1 isoforms adopt a compact architecture distinct from mammalian PIEZOs, that the pore-distal N-terminal blade is dispensable for mechanosensation, and that isoforms bend membranes differently, indicating an evolutionarily divergent way to build mechanosensitive channels from a single, highly spliced gene.