Study On The Gating Mechanisms Of Mechano-Gated Piezo Channels

Ion channels serve as molecular pores in the membranes of living cells.Ionic currents owing to these channels in and out of the cells generate electrical signals that induce cascades of intracellular events underlying many biological processes.The one gated by mechanical stretch is named as Mechano-gated ion channel,who plays critical roles in various physiological processes,such as touch and pain sensation,proprioception,blood pressure regulation,and osmoregulation.Piezo family of proteins is the long-sought-after mammalian excitatory mechano-gated cation channel.The mammalian Piezos contain over 2,500 amino acids and are predicted to have 30-40 transmembrane segments,without any notable sequence or structure homology in comparison with all known classes of ion channels or other protein families.The resolved cryo-electron microscopy(cryo-EM)structure of full-length mPiezo1(2,547 amino acids in each protomer)shows that,Piezo1 forms a homo-trimeric propeller-like structure,with a potential pore domain comprising the outer helix(OH),C-terminal extracellular domain(CED),inner helix(IH)and intracellular C-terminal domain(CTD),and a peripheral domain comprising the extracellular blade,the peripheral helices(PHs),the intracellular Beam and Anchor.However,the molecular bases and mechanisms that underlie their ion permeation and mechanotransduction have remained functionally undefined.In the present study,we identified the molecular bases of the ion-conducting pore module formed by the C-terminal region of ~350 residues and the mechanotransduction module formed by the large N-terminal region of ~2200 residues.Moreover,we found the IH of each protomer within the trimer contributing the pore-lining residues;the specific residues within the pore module that determine unitary conductance;the ion selectivity for divalent and monovalent cations and anions;the conformational change during gating of the pore;the key residues for gating inside the pore;as well as the critical domains and regulative residues for mechanotransduction.In conclusion,Our findings provide us a better understanding on Piezo1 channel of the pore properties,the mechanisms of ion conducting and selectivity,as well as the processes of mechanotransduction and gating.They may also offer the possibility for potential drug design and development targeting on Piezo channels.