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Ion Permeation Mechanism in Epithelial Calcium Channel TRVP6
#MMPMID29632318
Sakipov S
; Sobolevsky AI
; Kurnikova MG
Sci Rep
2018[Apr]; 8
(1
): 5715
PMID29632318
show ga
Calcium is the most abundant metal in the human body that plays vital roles as a
cellular electrolyte as well as the smallest and most frequently used signaling
molecule. Calcium uptake in epithelial tissues is mediated by tetrameric
calcium-selective transient receptor potential (TRP) channels TRPV6 that are
implicated in a variety of human diseases, including numerous forms of cancer. We
used TRPV6 crystal structures as templates for molecular dynamics simulations to
identify ion binding sites and to study the permeation mechanism of calcium and
other ions through TRPV6 channels. We found that at low Ca(2+) concentrations, a
single calcium ion binds at the selectivity filter narrow constriction formed by
aspartates D541 and allows Na(+) permeation. In the presence of ions, no water
binds to or crosses the pore constriction. At high Ca(2+) concentrations, calcium
permeates the pore according to the knock-off mechanism that includes formation
of a short-lived transition state with three calcium ions bound near D541. For
Ba(2+), the transition state lives longer and the knock-off permeation occurs
slower. Gd(3+) binds at D541 tightly, blocks the channel and prevents Na(+) from
permeating the pore. Our results provide structural foundations for understanding
permeation and block in tetrameric calcium-selective ion channels.
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