@article{6f521ea9aae047e5861184076aaa71a0,
title = "Identification of a unique Ca2+-binding site in rat acid-sensing ion channel 3",
abstract = "Acid-sensing ion channels (ASICs) evolved to sense changes in extracellular acidity with the divalent cation calcium (Ca2+) as an allosteric modulator and channel blocker. The channel-blocking activity is most apparent in ASIC3, as removing Ca2+ results in channel opening, with the site's location remaining unresolved. Here we show that a ring of rat ASIC3 (rASIC3) glutamates (Glu435), located above the channel gate, modulates proton sensitivity and contributes to the formation of the elusive Ca2+ block site. Mutation of this residue to glycine, the equivalent residue in chicken ASIC1, diminished the rASIC3 Ca2+ block effect. Atomistic molecular dynamic simulations corroborate the involvement of this acidic residue in forming a high-Affinity Ca2+ site atop the channel pore. Furthermore, the reported observations provide clarity for past controversies regarding ASIC channel gating. Our findings enhance understanding of ASIC gating mechanisms and provide structural and energetic insights into this unique calcium-binding site.",
author = "Zhicheng Zuo and Smith, {Rachel N.} and Zhenglan Chen and Agharkar, {Amruta S.} and Snell, {Heather D.} and Renqi Huang and Jin Liu and Gonzales, {Eric B.}",
note = "Funding Information: This research was supported by the American Heart Association Beginning Grant-In-Aid 12BGIA8820001, the Welch Foundation BK1736 (to E.B.G.), the Texas Alzheimer{\textquoteright}s Research and Care Consortium Investigator Grant Program (TARCC, to R.H.), and William and Ella Owens Medical Research Foundation (to R.H.). We thank Prof. David Sept at the University of Michigan for providing the python script that facilitates the correction of the van der Walls parameters regarding the Ca2+ dummy atom model, and acknowledge the Texas Advanced Computing Center (TACC) at the University of Texas at Austin and the University of North Texas (UNT){\textquoteright}s High Performance Computing Services (a division of the University Information Technology with additional support from UNT Office of Research and Economic Development) for providing computational resources that contributed to the simulation results reported within this paper. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-04424-0",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}