Analysis of an electrostatic mechanism for ΔpH dependent gating of the voltage-gated proton channel, HV1, supports a contribution of protons to gating charge

Sokolov, V.S.; Cherny, Vladimir V.; Ayuyan, Artem G.; DeCoursey, Thomas E.

doi:10.1016/j.bbabio.2021.148480

Cited by 9 publications

(14 citation statements)

References 89 publications

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“…However, Asp112, located in the S1 domain and conserved among the species, has been identified as a critical amino acid residue for the channel’s selectivity toward H + ions . The gating and permeation mechanisms are still unclear, although the detailed literature has discussed these subjects. − …”

Section: Introductionmentioning

confidence: 99%

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Llanos

Ventura

Martín

et al. 2022

J. Chem. Inf. Model.

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The human voltage-gated proton channel (hHv1) is a highly selective ion channel codified by the HVCN1 gene. It plays a fundamental role in several physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Moreover, in humans, a higher hHv1 expression/function has been reported in several types of cancer cells. Here we report a multitemplate homology model of the hHv1 channel, built and refined as a dimer in Rosetta. The model was then subjected to extensive Gaussian accelerated molecular dynamics (GaMD) for enhanced conformational sampling, and representative snapshots were extracted by clustering analysis. Combining different structure-and sequence-based methodologies, we predicted a putative ATP-binding site located on the intracellular portion of the channel. Furthermore, GaMD simulations of the ATP-bound dimeric hHv1 model showed that ATP interacts with a cluster of positively charged residues from the cytoplasmic N and C terminal segments. According to the in silico predictions, we found that 3 mM intracellular ATP significantly increases the H + current mediated by the hHv1 channel expressed in HEK293 cells and measured by the patch-clamp technique in an inside-out configuration (2.86 ± 0.63 fold over control at +40 mV). When ATP was added on the extracellular side, it was not able to activate the channel supporting the idea that the ATP-binding site resides in the intracellular face of the hHV1 channel. In a physiological and pathophysiological context, this ATP-mediated modulation could integrate the cell metabolic state with the H + efflux, especially in cells where hHv1 channels are relevant for pH regulation, such as pancreatic β-cells, immune cells, and cancer cells.

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Section: Introductionmentioning

confidence: 99%

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect

Llanos

Ventura

Martín

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…Increasing symmetrical pH across the membrane (when pH i = pH o , also denoted pH i//o ) also enhances H V 1 activation. 27,61,62 In our group, preliminary measurements of the conductance of hH V 1m at symmetrical pH conditions show that the channel already opens at pH 5.5 and confirm a higher probability for the channel to open with increasing pH (Fig. S1, ESI†).…”

Section: Resultsmentioning

confidence: 78%

“…However, our simulations suggest that during the pH (only)-dependent activation of hH V 1 only the second S4 arginine passes the HG from the intra- to the extracellular side of the channel, in agreement with the “one-click” model (as illustrated in ref. 88 and 62). The activated state identified in our simulations is consistent with experimental accessibility data of the three S4 Arg, indicating that the two outermost Arg (R1 and R2) are accessible to the solvent, but R3 is accessible only to the internal solution after gating.…”

Section: Resultsmentioning

confidence: 98%

“…By changing their PS near the activation pH-range, some of these residues might contribute to modify the charge at the internal (H99, H167) or external (D123, D130, E192) membrane that is perceived by the voltage-sensor (the three S4 arginines) in the voltage-dependent gating, as proposed in the electrostatic model of ΔpH gating in ref. 62. The second group consists of the AAs in the channel pore.…”

Section: Resultsmentioning

confidence: 99%

“…Chem. Phys., 2022, 24, 9964-9977 | 9973to modify the charge at the internal (H99, H167) or external (D123, D130, E192) membrane that is perceived by the voltagesensor (the three S4 arginines) in the voltage-dependent gating, as proposed in the electrostatic model of DpH gating in ref 62…”

mentioning

confidence: 99%

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