CLIC-2 modulates cardiac ryanodine receptor Ca2+ release channels.
We have examined the biochemical and functional properties of the recently identified, uncharacterised CLIC-2 protein. Sequence alignments showed that CLIC-2 has a high degree of sequence similarity with CLIC-1 and some similarity to the omega class of glutathione transferases (GSTO). A homology model of CLIC-2 based on the crystal structure of CLIC-1 suggests that CLIC-2 belongs to the GST structural family but, unlike the GSTs, CLIC-2 exists as a monomer. It also has an unusual enzyme activity profile. While the CXXC active site motif is conserved between CLIC-2 and the glutaredoxins, no thiol transferase activity was detected. In contrast, low glutathione peroxidase activity was recorded. CLIC-2 was found to be widely distributed in tissues including heart and skeletal muscle. Functional studies showed that CLIC-2 inhibited cardiac ryanodine receptor Ca2+ release channels in lipid bilayers when added to the cytoplasmic side of the channels and inhibited Ca2+ release from cardiac sarcoplasmic reticulum vesicles. The inhibition of RyR channels was reversed by removing CLIC-2 from the solution or by adding an anti-CLIC-2 antibody. The results suggest that one function of CLIC-2 might be to limit Ca2+ release from internal stores in cells.
Board
Philip G
PG
Division of Molecular Bioscience, John Curtin School of Medical Research, The Australian National University, P.O. Box 334, Canberra, ACT 2601, Australia. philip.board@anu.edu.au
Coggan
Marjorie
M
Watson
Sarah
S
Gage
Peter W
PW
Dulhunty
Angela F
AF
D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D018118:Chloride Channels / Q000502:physiology*; D017124:Conserved Sequence; D003593:Cytoplasm / Q000378:metabolism; D005982:Glutathione Transferase; D006801:Humans; D018482:Muscle, Skeletal / Q000737:chemistry; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D016415:Sequence Alignment; D014018:Tissue Distribution
C108828:CLIC2 protein, human; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D019837:Ryanodine Receptor Calcium Release Channel; D005982:Glutathione Transferase; D002118:Calcium