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Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1009-1014. doi: 10.1073/pnas.1616191114. Epub 2017 Jan 17.

Tuning the ion selectivity of two-pore channels.

Guo J1, Zeng W1,2, Jiang Y3,2.

Author information

1
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040.
2
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040.
3
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040; youxing.jiang@utsouthwestern.edu.

Abstract

Organellar two-pore channels (TPCs) contain two copies of a Shaker-like six-transmembrane (6-TM) domain in each subunit and are ubiquitously expressed in plants and animals. Interestingly, plant and animal TPCs share high sequence similarity in the filter region, yet exhibit drastically different ion selectivity. Plant TPC1 functions as a nonselective cation channel on the vacuole membrane, whereas mammalian TPC channels have been shown to be endo/lysosomal Na+-selective or Ca2+-release channels. In this study, we performed systematic characterization of the ion selectivity of TPC1 from Arabidopsis thaliana (AtTPC1) and compared its selectivity with the selectivity of human TPC2 (HsTPC2). We demonstrate that AtTPC1 is selective for Ca2+ over Na+, but nonselective among monovalent cations (Li+, Na+, and K+). Our results also confirm that HsTPC2 is a Na+-selective channel activated by phosphatidylinositol 3,5-bisphosphate. Guided by our recent structure of AtTPC1, we converted AtTPC1 to a Na+-selective channel by mimicking the selectivity filter of HsTPC2 and identified key residues in the TPC filters that differentiate the selectivity between AtTPC1 and HsTPC2. Furthermore, the structure of the Na+-selective AtTPC1 mutant elucidates the structural basis for Na+ selectivity in mammalian TPCs.

KEYWORDS:

crystal structure; ion selectivity; two-pore channel

PMID:
28096396
PMCID:
PMC5293054
DOI:
10.1073/pnas.1616191114
[Indexed for MEDLINE]
Free PMC Article

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