The glutathione transferase structural family includes a nuclear chloride channel and a ryanodine receptor calcium release channel modulator.
The ubiquitous glutathione transferases (GSTs) catalyze glutathione conjugation to many compounds and have other diverse functions that continue to be discovered. We noticed sequence similarities between Omega class GSTs and a nuclear chloride channel, NCC27 (CLIC1), and show here that NCC27 belongs to the GST structural family. The structural homology prompted us to investigate whether the human Omega class glutathione transferase GSTO1-1 forms or modulates ion channels. We find that GSTO1-1 modulates ryanodine receptors (RyR), which are calcium channels in the endoplasmic reticulum of various cells. Cardiac RyR2 activity was inhibited by GSTO1-1, whereas skeletal muscle RyR1 activity was potentiated. An enzymatically active conformation of GSTO1-1 was required for inhibition of RyR2, and mutation of the active site cysteine (Cys-32 --> Ala) abolished the inhibitory activity. We propose a novel role for GSTO1-1 in protecting cells containing RyR2 from apoptosis induced by Ca(2+) mobilization from intracellular stores.
Dulhunty
A
A
John Curtin School of Medical Research, Australian National University, P. O. Box 334, Canberra, Australian Capital Territory 2601, Australia.
Gage
P
P
Curtis
S
S
Chelvanayagam
G
G
Board
P
P
D000595:Amino Acid Sequence; D000818:Animals; D018118:Chloride Channels / Q000737:chemistry* / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012756:Sheep; D013045:Species Specificity; D013552:Swine
C501966:CLIC1 protein, human; D018118:Chloride Channels; D019837:Ryanodine Receptor Calcium Release Channel; D005982:Glutathione Transferase