The Structure of a Conserved Piezo Channel Domain Reveals a Topologically Distinct β Sandwich Fold

Abstract

Summary Piezo has recently been identified as a family of eukaryotic mechanosensitive channels composed of subunits containing over 2000 amino acids, without recognizable sequence similarity to other channels. Here, we present the crystal structure of a large, conserved extramembrane domain located just before the last predicted transmembrane helix of C. elegans PIEZO, which adopts a novel beta sandwich fold. The structure was also determined of a point mutation located on a conserved surface at the position equivalent to the human PIEZO1 mutation found in Dehydrated Hereditary Stomatocytosis (DHS) patients (M2225R). While the point mutation does not change the overall domain structure, it does alter the surface electrostatic potential that may perturb interactions with a yet-to-be identified ligand or protein. The lack of structural similarity between this domain and any previously characterized fold, including those of eukaryotic and bacterial channels, highlights the distinctive nature of the Piezo family of eukaryotic mechanosensitive channels.

The biophysics of piezo1 and piezo2 mechanosensitive channels

“…Moreover, point mutations in the CTL2 domain of human piezo proteins are involved in the gating kinetics of the channel (Bae et al, 2011). The CTL2 model published by Kamajaya et al (2014) establishes that the region adopts a topologically distinct β-sandwich fold with three sheets, where sheet 1 is nearly parallel to sheet 2 and perpendicular to sheet 3 (see figure 2). This fold does not appear to be shared with any other family of proteins in eukaryotes, thus contributing to highlight the distinctive nature of…”

“…Piezo proteins are composed by about 2500-2800 amino acids and are predicted to encompass between 26 and 40 transmembrane domains (see table 1) (Kamajaya et al, 2014). Noticeably, human piezo1 and piezo2 are the two human proteins predicted to show the highest number of transmembrane segments (Volkers et al, 2014).…”

“…Recently, Kamajaya and coworkers solved the three-dimensional structure of the soluble C-terminal loop 2 (CTL2) from the Caenorhabditis elegans piezo. The loop is located just before the last putative transmembrane helix and the C-terminal tail (see figure 1) (Kamajaya et al, 2014). CTL2 is the largest conserved loop (about 250 aa) among piezo homologs, showing a moderate degree of sequence conservation that suggests a key role in the protein functionality.…”

“…piezo family (Kamajaya et al, 2014). It is worth noting that in human piezo1 CTL2, the substitution of methionine with arginine in position 2225 (M2225R) causes dehydrated hereditary stomatocytosis (DHS) disease (see table 3).…”

A Short Guide to Electrophysiology and Ion Channels

“…There are two mammalian mechanosensitive ion channels, namely Piezo1 and Piezo2, which consist of some 2,500 to 2,800 amino acids. It is believed they hold between 26 to 40 transmembrane domains (113). Piezo1 and 2 are expressed in the lungs and bladder, two organs that both hold vital mechanosensory functions.…”