Several proteins including podocin (8.A.21.1.2), nephrin (8.A.23.1.33), CD2AP (8.A.34.1.5) and TRPC6 form a macromolecular assembly that constitutes the slit-diaphragm in podocytes that resembles tight junctions ( Mulukala et al. TRPC6 may regulate the glomerular filtration rate by modulating mesangial cell contractile function through multiple Ca 2+ signaling pathways ( Li et al. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening ( Tang et al. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The structure shows a two-layer architecture in which the bell-shaped cytosolic layer holds the transmembrane layer. 2018 presented the structure of the human TRPC6 homotetramer in complex with a high-affinity inhibitor, BTDM, solved by single-particle cryo-electron microscopy to 3.8 Å resolution. Mutation causes a particularly aggressive form of familial focal segmental glomerulosclerosis ( Winn et al., 2005 Mukerji et al., 2007). Non-selective cation channel that is directly activated byĭiacylglycerol (DAG ( Szabó et al. Transient receptor potential canonical-6, TRPC6, a TRPC3 is primarily gated by lipids, and its surface expression is dependent on cholesterol ( Clarke et al. Structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets revealed different conformations of the transmembrane domain ( Guo et al. The GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. These calcium sensors are structurally and functionally conserved in TRPC6. They identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. 2022 reported the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans. TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels. This channel may be present in mitochondria ( Parrasia et al. The cytoplasmic domain allosterically modulates channel gating ( Sierra-Valdez et al. 2018 identified two lipid binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The structure in a lipid-occupied, closed state has been solved at 3.3 Å resolution. TRPC channels are involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia ( Fan et al. The channel may have a large internal chamber surrounded by signal sensing antennas ( Mio et al. Gate and the selectivity filter has been proposed ( Ko et al. A structural model of the TRPC3 permeation pathway based on a sodium channel (TC# 1.A.1.14.5) with a localized selectivityįilter and an occluding gate with evidence for allosteric coupling between the TRPC3 store-operated non-selective cation channel (activated by thapsigargin and 2 acyl glycerol forms a heteromeric channel with TrpC1, TC #1.A.4.1.3) ( Liu et al., 2005).
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