TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.A.75.1.1









Piezo1 (FAM38a) mechanosensitive ion channel of 2521 aas and ~ 38 TMSs in a 4 x 9 + 2 TMS arrangement. The protein has a C-terminal DUF3595 (pfam 12166) domain (Coste et al., 2010).  Fam38A expression may cause increased cell migration and metastasis in lung tumours (McHugh et al. 2012). It is imporatnt for gastrointestinal tract function (Alcaino et al. 2017). A high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer has been determined (Saotome et al. 2017). The detergent-solubilized complex adopts a three-blade propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-TMS bundles termed 'Piezo repeats'. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically (Saotome et al. 2017). The Piezo1 pore remains fully open if only one subunit is activated, for example by binding the agonist, Yoda1 (Lacroix et al. 2018). The channel mediates uterine artery shear stress mechanotransduction and vasodilation during pregnancy (John et al. 2018). The channel can transport alkali monovalent cations (Na+, K+, Rb+, Cs+ and Li+ as well as Ca2+, tetramethyl ammonium and tetraethyl ammonium, although these last four cations are transported at slow rates (Gnanasambandam et al. 2017). Agonist-induced Piezo1 activation promotes mitochondrial-dependent apoptosis in vascular smooth muscle cells (Yin et al. 2022). Piezo1 is the stretch activated Ca2+ channel in red blood cells that mediates homeostatic volume control. Vaisey et al. 2022 studied the organization of Piezo1 in red blood cells. Piezo1 adopts a non-uniform distribution on the red blood cell surface, with a bias toward the biconcave 'dimple'. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias toward the dimple. This bias can be explained by 'curvature coupling' between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it colocalize with F-actin, Spectrin, or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell (Vaisey et al. 2022). Mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons (Della Pietra et al. 2023). Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by high reticulocyte count, a tendency to macrocytosis, and mild jaundice, as well as by other variably penetrant clinical features, such as perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload (Andolfo et al. 2023). Mechanical stretching induces fibroblast apoptosis by activating Piezo1 and then destroying the actin cytoskeleton (Li et al. 2023). Force-induced motions of the PIEZO1 blade have been probed with fluorimetry (Ozkan et al. 2023). Low-intensity fluid shear stress causes a unique form of mechanical stress to the cell.  A light-gated mouse PIEZO1 channel, in which an azobenzene-based photoswitch covalently tethered to an engineered cysteine, Y2464C, localized at the extracellular apex of the TMS 38, rapidly triggers channel gating upon 365-nm-light irradiation. Peralta et al. 2023 provided evidence that this light-gated channel recapitulates mechanically-activated PIEZO1 functional properties, and show that light-induced molecular motions are similar to those evoked mechanically. GenEPi is a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. Yaganoglu et al. 2023 demonstrated that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo (Yaganoglu et al. 2023). Membrane stretch provides a mechanism for activation of PIEZO1 channels in chondrocytes (Savadipour et al. 2023).  Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the authors mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease (Zhou et al. 2023). PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion (Carrisoza-Gaytan et al. 2024).

Eukaryota
Metazoa, Chordata
Piezo1 of Homo sapiens (Q92508)
1.A.75.1.2









Piezo2 (FAM38b) of 2,752 aas and 37 TMSs in a 4 x 9 + 1 TMS arrangement. It is the major transducer of mechanical force for touch sensation (Ranade et al. 2014) and is a rapidly adapting mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors called Merkel cell neurite complexes.  Ranade et al. 2014 showed that touch and pain are mediated by distinct receptors. Piezo2 mediates alloknesis (pathological sensations including itch of dry skin (Feng et al. 2018). In fact, PIEZO2 is a mechanosensitive cation channel that plays a key role in sensing touch, tactile pain, breathing and blood pressure. Wang et al. 2019 described the cryo-EM structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 TMSs (38 per protomer). TMSs 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TMS38 and the C-terminal domain are surrounded by the anchor domain and TMS37, and they enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 revealed that the transmembrane constriction site might act as a gate that is controlled by the cap domain (Wang et al. 2019). Up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of neuralgia (Liu et al. 2021). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2 (Verkest et al. 2022). Human cutaneous mechanoreceptors can perform mechanotransduction already during embryonic development (García-Mesa et al. 2022). Genetic alterations of Piezo2 have been reported in human cancer (Liu et al. 2022). Piezo2 transmembrane excitatory mechanosensitive ion channels have been identified as the principal mechanotransduction channels for proprioception (Sonkodi 2022). Mechanical distension/stretch in the colon provokes visceral hypersensitivity and pain. Xie et al. reported that mechanosensitive Piezo2 channels, expressed by TRPV1-lineage nociceptors, are involved in visceral mechanical nociception and hypersensitivity (Xie et al. 2023). Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC (246 aas and 2 - 3 C-terminal TMSs and MDFI ) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the authors mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease (Zhou et al. 2023).  PIEZO2 expression is an independent biomarker prognostic for gastric cancer and represents a potential therapeutic target (Zhang et al. 2024).

Eukaryota
Metazoa, Chordata
PIEZO2 of Homo sapiens (Q9H5I5) + MDFIC or MDFI (Uniprot acc #s Q9P1T7 or Q99750), both of 246 aas with 2 - 3 C-terminal TMSs as auxillary proteins.
1.A.75.1.3









Piezo mechanosensitive ion channel of 2760 aas and ~38 TMSs in a 4 x 9 + 2 TMS arrangement (Kim et al., 2012)

Eukaryota
Metazoa, Arthropoda
Piezo (CG8486) of Drosophila melanogaster (Q9VLS3)
1.A.75.1.4









Piezo protein homolog of 2462 aas and possibly 42 TMSs in an approximately 4 x 10 + 2 TMS arrangement. This piezo-like protein suppresses systemic movement of plant viruses in Arabidopsis thaliana (Zhang et al. 2019). It plays a role in root cap mechanotransduction (Fang et al. 2021) and modulates vacuole morphology during tip growth (Radin et al. 2021). Arabidopsis PIEZO1 localizes to the tonoplast and is required for vacuole tubulation in the tips of pollen tubes.

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Eukaryota
Viridiplantae, Streptophyta
UP of Arabidodopsis thaliana (F4IN58)
1.A.75.1.5









Piezo_RRas_bdg domain-containing protein of 2544 aas and ~ 40 TMSs.

Eukaryota
Ciliophora
Piezo homolog of Paramecium tetraurelia (A0EF36)
1.A.75.1.6









Piezo-like protein of 2724 aas and ~ 43 TMSs (Prole and Taylor 2013).

Eukaryota
Euglenozoa
Piezo of Trypanosoma cruzi (Q4E330)
1.A.75.1.7









Piezo homologue of 2382 aas and ~ 38 TMSs in a 4 x 9 + 2 TMS arrangement.

Eukaryota
Metazoa, Nematoda
Piezo homologue of Ascaris suum (F1KQU6)
1.A.75.1.8









Mechanosensitive piezo channel protein, isoform a, of 2438 aas.  The C-terminal extracellular domain (before the last TMS) has a β-sandwich fold (Kamajaya et al. 2014). It coordinates multiple reproductive tissues to govern ovulation (Bai et al. 2020).

Eukaryota
Metazoa, Nematoda
Piezo of Caenorhabditis elegans
1.A.75.1.9









Piezo channel of 2013 aas and about 21 TMSs.

Eukaryota
Metazoa, Platyhelminthes
Piezo of Schistosoma mansoni (Blood fluke)
1.A.75.1.10









Piezo channel of 2470 aas

Eukaryota
Ciliophora
Piezo of Paramecium tetraurelia
1.A.75.1.11









Piezo channel of 2598 aas (Prole and Taylor 2013).

Eukaryota
Euglenozoa
Piezo of Trypanosoma cruzi
1.A.75.1.12









Piezo-like channel protein of 2533 aas and ~42 TMSs.

Eukaryota
Euglenozoa
Piezo protein of Leishmania donovani
1.A.75.1.13









Uncharacterized piezo channel homologue of 1931 aas and ~ 37 putative TMSs.

Eukaryota
Euglenozoa
UP of Bodo saltans
1.A.75.1.14









Piezo1 (Fam38a) of 2547 aas and ~ 38 TMSs. The three-bladed propeller-like cryoEM structure and its mechanotransduction components are known (Zhao et al. 2018). There are nine repeat units consisting of four transmembrane helices, each of which is termed a transmembrane helical unit (THU). These assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect the THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Thus, Piezo1 possesses a 38-transmembrane-helix topology with mechanotransduction components that enable a lever-like mechanogating mechanism (Zhao et al. 2018). The Piezo1 pore remains fully open if only one of the three subunits is activate, for example by binding the agonist, Yoda1 (Lacroix et al. 2018). Piezo1 mediates endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation (Yang et al. 2021).

Eukaryota
Metazoa, Chordata
Piezo1 of Mus musculus
1.A.75.1.15









Piezo-type mechanosensitive ion channel component 2 of 2023 aas and ~ 31 putative TMSs. G. soya and other plants often have multiple Piezo proteins.

Eukaryota
Viridiplantae, Streptophyta
Piezo of Glycine soja
1.A.75.1.16









Uncharacterized protein of 2321 aas and ~35 TMSs.

Eukaryota
Ciliophora
UP of Stentor coeruleus
1.A.75.1.17









Piezo homologue of 3315 aas and ~48 TMSs.

Eukaryota
Piezo of Vitrella brassicaformis
1.A.75.1.18









Piezo homologue of 2620 aas and ~47 TMSs.

Eukaryota
Euglenozoa
Piezo of Leptomonas pyrrhocoris
1.A.75.1.19









Fibronectin, type III of 2452 aas and ~38 TMSs iin a 4 x 9 + 2 TMS arrangement.

Eukaryota
Viridiplantae, Chlorophyta
Piezo homologue of Ostreococcus tauri
1.A.75.1.20









Piezo homologue of 2888 aas and ~40 TMSs.

Eukaryota
Ciliophora
Piezo of Pseudocohnilembus persalinus
1.A.75.1.21









Piezo homologue of 2401 aas and ~ 38 TMSs.

Eukaryota
Evosea
Piezo of Entamoeba histolytica
1.A.75.1.22









Piezo2-like protein of 2811 aas and ~ 40 TMSs.

Eukaryota
Piezo2 of Nannochloropsis gaditana
1.A.75.1.23









Uncharacterized protein of 2710 aas and ~ 40 TMSs.

Eukaryota
Oomycota
UP of Aphanomyces invadans
1.A.75.1.24









Uncharacterized protein of 2121 aas and ~ 42 TMSs, possibly with 10 4 TMS repeats.

Eukaryota
Parabasalia
UP of Tritrichomonas foetus
1.A.75.1.25









Piezo-type mechanosensitive ion channel homolog isoform X1 of 2572 aas and ~38 TMSs with nine 2 + 1 + 1 TMS repeat units followed by 2 C-terminal TMSs that comprise the channel.  It modulates vacuole morphology during tip growth (Radin et al. 2021).

Eukaryota
Viridiplantae, Streptophyta
Piezo 1 of Physcomitrium patens (moss)