Biology:PIEZO1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

PIEZO1 is a mechanosensitive ion channel protein that in humans is encoded by the gene PIEZO1. PIEZO1 and its close homolog PIEZO2 were cloned in 2010, using an siRNA-based screen for mechanosensitive ion channels.[1]

Structure and function

PIEZO1 (this gene) and PIEZO2 share 47% identity with each other and they have no similarity to any other protein and contain no known protein domains. They are predicted to have 24-36 transmembrane domains, depending on the prediction algorithm used. In the original publication the authors were careful not to call the piezo proteins ion channels, but a more recent study by the same lab convincingly demonstrated that indeed PIEZO1 is the pore-forming subunit of a mechanosensitive channel.[2] This new " PIEZO" family is catalogued as InterPro: IPR027272 and TCDB Template:TCDB. PIEZO1 homologues are found in C. elegans and Drosophila, which, like other invertebrates, have a single PIEZO protein.

It is known (PDB: 6B3R​) that PIEZO1 channel is a three-bladed propeller-like structure. A lever-like mechanogating mechanism is assumed.[3][4]

Image of PIEZO1 homotrimer (left: from the side, right: from the top) created with PyMOL from PDB: 5Z10​.

Tissue distribution

PIEZO1 is expressed in the lungs, bladder and skin, where mechanosensation has important biological roles. Unlike PIEZO2 which is highly expressed in sensory dorsal root ganglia, PIEZO1 is not expressed in sensory neurons.[1] Consequently PIEZO1 plays a significant role in multiple neurobiological processes including axon regeneration, neural stem cells differentiation and neurological diseases progression.[5]

Clinical significance

PIEZO1 is also found in red blood cells, and gain of function mutations in the channels are associated with hereditary xerocytosis or stomatocytosis.[6][7][8] PIEZO1 channels are pivotal integrators in vascular biology.[9]

An allele of PIEZO1, E756del, results in a gain-of-function mutation, resulting in dehydrated RBCs and conveying resistance to Plasmodium. This allele has been demonstrated in vitro to prevent cerebral malaria infection.[10]

PIEZO1 has been implicated in extrusion of epidermal cells when a layer becomes too confluent to preserve normal skin homeostasis. This acts to prevent excess proliferation of skin tissue, and has been implicated in cancer biology as a contributing factor to metastases by assisting living cells in escaping from a monolayer.[11]

Expression of murine PIEZO1 in mouse innate immune cells is essential for their function, a role mediated by sensing mechanical cues. Deficiency in PIEZO1 in mice lead to increased susceptibility of myeloid cells to infection by Pseudomonas aeruginosa.[12]

Lymphatic malformation 6 syndrome is caused by mutations in PIEZO1 and was characterized in 2015.[13]

PIEZO1 has been proposed as a therapeutic target for Alzheimer's disease. The build-up of amyloid-β plaques which stiffens the brain's structure. Microglial maintenance cells, which express PIEZO1, detect this stiffness via PIEZO1-enabled mechanosensation and in response surround, compact, and phagocytosize the plaques. Removal of the gene which codes for PIEZO1 in microglia decreases plaque clearance and hastens cognitive decline in rats.[14]

Ligands

Agonists

Antagonists

References

  1. ↑ 1.0 1.1 "Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels". Science 330 (6000): 55–60. October 2010. doi:10.1126/science.1193270. PMID 20813920. Bibcode: 2010Sci...330...55C. 
  2. ↑ "Piezo proteins are pore-forming subunits of mechanically activated channels". Nature 483 (7388): 176–181. February 2012. doi:10.1038/nature10812. PMID 22343900. Bibcode: 2012Natur.483..176C. 
  3. ↑ "The mechanosensitive Piezo1 channel: a three-bladed propeller-like structure and a lever-like mechanogating mechanism". The FEBS Journal 286 (13): 2461–2470. July 2019. doi:10.1111/febs.14711. PMID 30500111. 
  4. ↑ "A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel". Nature Communications 9 (1): 1300. April 2018. doi:10.1038/s41467-018-03570-9. PMID 29610524. Bibcode: 2018NatCo...9.1300W. 
  5. ↑ Bryniarska-Kubiak, Natalia; Kubiak, Andrzej; Basta-Kaim, Agnieszka (October 2023). "Mechanotransductive Receptor Piezo1 as a Promising Target in the Treatment of Neurological Diseases". Current Neuropharmacology 21 (10): 2030–2035. doi:10.2174/1570159X20666220927103454. PMID 36173070. 
  6. ↑ "Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis". Blood 120 (9): 1908–1915. August 2012. doi:10.1182/blood-2012-04-422253. PMID 22529292. 
  7. ↑ "Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1". Proceedings of the National Academy of Sciences of the United States of America 110 (12): E1162–E1168. March 2013. doi:10.1073/pnas.1219777110. PMID 23487776. Bibcode: 2013PNAS..110E1162B. 
  8. ↑ "Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels". Nature Communications 4: 1884. 2013. doi:10.1038/ncomms2899. PMID 23695678. Bibcode: 2013NatCo...4.1884A. 
  9. ↑ "Piezo1 integration of vascular architecture with physiological force". Nature 515 (7526): 279–282. November 2014. doi:10.1038/nature13701. PMID 25119035. Bibcode: 2014Natur.515..279L. 
  10. ↑ "Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection". Cell 173 (2): 443–455.e12. April 2018. doi:10.1016/j.cell.2018.02.047. PMID 29576450. 
  11. ↑ "Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia". Nature 484 (7395): 546–549. April 2012. doi:10.1038/nature10999. PMID 22504183. Bibcode: 2012Natur.484..546E. 
  12. ↑ "Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity". Nature 573 (7772): 69–74. September 2019. doi:10.1038/s41586-019-1485-8. PMID 31435009. Bibcode: 2019Natur.573...69S. 
  13. ↑ "Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis". Nature Communications 6: 8085. September 2015. doi:10.1038/ncomms9085. PMID 26333996. Bibcode: 2015NatCo...6.8085F. 
  14. ↑ Hu, Jin; Chen, Qiang; Zhu, Hongrui; Hou, Lichao; Liu, Wei; Yang, Qihua; Shen, Huidan; Chai, Guolin et al. (January 2023). "Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease". Neuron 111 (1): 15–29.e8. doi:10.1016/j.neuron.2022.10.021. ISSN 0896-6273. PMID 36368316. 
  15. ↑ "Chemical activation of the mechanotransduction channel Piezo1". eLife 4. May 2015. doi:10.7554/eLife.07369. PMID 26001275. 
  16. ↑ Bae, Chilman; Sachs, Frederick; Gottlieb, Philip A. (2011-07-26). "The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4". Biochemistry 50 (29): 6295–6300. doi:10.1021/bi200770q. ISSN 0006-2960. PMID 21696149. 
  17. ↑ Gnanasambandam, Radhakrishnan; Ghatak, Chiranjib; Yasmann, Anthony; Nishizawa, Kazuhisa; Sachs, Frederick; Ladokhin, Alexey S.; Sukharev, Sergei I.; Suchyna, Thomas M. (2017-01-10). "GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels". Biophysical Journal 112 (1): 31–45. doi:10.1016/j.bpj.2016.11.013. ISSN 0006-3495. PMID 28076814. Bibcode: 2017BpJ...112...31G. 
  18. ↑ Evans, Elizabeth L.; Cuthbertson, Kevin; Endesh, Naima; Rode, Baptiste; Blythe, Nicola M.; Hyman, Adam J.; Hall, Sally J.; Gaunt, Hannah J. et al. (May 2018). "Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation". British Journal of Pharmacology 175 (10): 1744–1759. doi:10.1111/bph.14188. ISSN 1476-5381. PMID 29498036. 



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