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@ARTICLE{Chaves:878597,
author = {Chaves, Gustavo and Bungert‐Plümke, Stefanie and
Franzen, Arne and Mahorivska, Iryna and Musset, Boris},
title = {{Z}inc modulation of proton currents in a new
voltage‐gated proton channel suggests a mechanism of
inhibition},
journal = {The FEBS journal},
volume = {287},
number = {22},
issn = {1742-4658},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {FZJ-2020-02935},
pages = {4996-5018},
year = {2020},
abstract = {The HV1 voltage‐gated proton (HV1) channel is a key
component of the cellular proton extrusion machinery and is
pivotal for charge compensation during the respiratory burst
of phagocytes. The best‐described physiological inhibitor
of HV1 is Zn2+. Externally applied ZnCl2 drastically reduces
proton currents reportedly recorded in Homo sapiens, Rattus
norvegicus, Mus musculus, Oryctolagus cuniculus, Rana
esculenta, Helix aspersa, Ciona intestinalis, Coccolithus
pelagicus, Emiliania huxleyi, Danio rerio, Helisoma
trivolvis, and Lingulodinium polyedrum, but with
considerable species variability. Here, we report the
effects of Zn2+ and Cd2+ on HV1 from Nicoletia phytophila,
NpHV1. We introduced mutations at potential Zn2+
coordination sites and measured Zn2+ inhibition in different
extracellular pH, with Zn2+ concentrations up to 1000 μm.
Zn2+ inhibition in NpHV1 was quantified by the slowing of
the activation time constant and a positive shift of the
conductance–voltage curve. Replacing aspartate in the
S3‐S4 loop with histidine (D145H) enhanced both the
slowing of activation kinetics and the shift in the
voltage–conductance curve, such that Zn2+ inhibition
closely resembled that of the human channel. Histidine is
much more effective than aspartate in coordinating Zn2+ in
the S3‐S4 linker. A simple Hodgkin Huxley model of NpHV1
suggests a decrease in the opening rate if it is inhibited
by zinc or cadmium. Limiting slope measurements and
high‐resolution clear native gel electrophoresis (hrCNE)
confirmed that NpHV1 functions as a dimer. The data support
the hypothesis that zinc is coordinated in between the dimer
instead of the monomer. Zinc coordination sites may be
potential targets for drug development.},
cin = {IBI-1},
ddc = {610},
cid = {I:(DE-Juel1)IBI-1-20200312},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32160407},
UT = {WOS:000558784200001},
doi = {10.1111/febs.15291},
url = {https://juser.fz-juelich.de/record/878597},
}