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- W2912125653 abstract "Voltage-gated calcium channels (CaV) consist of four homologous but non-identical repeats (I, II, III, IV), each containing a separate voltage-sensing domain (VSD) arranged around the common channel pore. Within each VSD the positive gating charges (R1, R2, R3, R4) in the transmembrane helix S4 sequentially interact with negative counter-charges in helices S2 and S3 to support the movement of the gating charges across the electrical field of the membrane and thus to activate or deactivate the channel. Previously we identified an interaction between R1 and R2 with aspartate 1196 (D4) in S3 of the VSD-IV of CaV1.1 that is critical for modulation of voltage-sensitivity and current-density by alternative splicing in the IVS3-S4 linker. Using molecular structure modeling we now identified an additional interaction with a glutamate (E216) in S5 of VSD-I that participates in the R1/R2-D4 interaction of VSD-IV. Charge-neutralization (E216Q) or substitution with alanine (E216A) in CaV1.1e caused a 7mV and 16mV, respectively, right-shift of voltage-dependence of activation and a 30 % reduction in current density. This effect is specific to the splice variant lacking exon 29 and is quantitatively in the same range as previously observed when R1, R2, or D4 were mutated; indicating that this trans-domain interaction between repeats I and IV participates in the voltage-dependent gating and its modulation by alternative splicing. Structure models of CaV1.1 in the activated and pre-open state show that the four VSD differ greatly regarding their intra-domain interactions, consistent with their specific contributions to CaV1.1 gating properties. The newly discovered inter-domain interaction is unique for VSD-I and IV. Together in silico structure modelling of this pseudo-tetrameric ion channel revealed hitherto not appreciated differences between the VSDs and a functional inter-domain interaction. Support: Austrian Science Fund (FWF) grant P30402." @default.
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- W2912125653 date "2019-02-01" @default.
- W2912125653 modified "2023-10-18" @default.
- W2912125653 title "Structure Modelling of CaV1.1 Reveals Functional Trans-Domain Interactions Involved in Voltage Sensing" @default.
- W2912125653 doi "https://doi.org/10.1016/j.bpj.2018.11.636" @default.
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