Allosteric switching of Ca2+ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation

ABSTRACT: Ion channels possess selectivity filters that are hardwired to ensure the selective passage of ions. Lysosomal two-pore channels are unusual as they are able to switch their cation selectivity in an agonist-specific manner, allowing differential control of organellar activity. TPC2 is permeable to Ca2+ when activated by the calcium-mobilizing messenger NAADP, but largely Na+-selective when activated by the signaling lipid PI(3,5)P2. Co-stimulation increases Ca2+ but not Na+ permeability; however, the molecular basis for these specificity switches is not well understood. Here we show that mutation of TPC2 residues within the distal cytosolic linker, which connects the first voltage-sensing-like domain to the pore, rendered TPC2 largely unable to discriminate its agonists and highly calcium-

SUBMITTER: Qianru Mu 

PROVIDER: S-SCDT-10_1038-S44318-026-00882-1 | biostudies-other |

REPOSITORIES: biostudies-other