Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Modulates the activity of RYR2 and inhibits calcium influx. (updated: Sept. 13, 2005)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
This protein is annotated as membranous in Gene Ontology.
Total structural coverage: 100%
No model available.
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The reference OMIM entry for this protein is 300138
Chloride intracellular channel 2; clic2
Xap121
DESCRIPTION
The CLIC2 gene encodes a protein that belongs to a class of soluble and membrane-bound proteins named because the first members of this family formed intracellular chloride channels. The CLIC2 protein is structurally similar to CLIC1 (
602872) and to a form of glutathione transferase (GSTO1;
605482), but has no transferase activity. CLIC2 functions as a regulator of calcium homeostasis in cardiac myocytes via interaction with the cardiac ryanodine receptor (RYR2;
180902) (summary by Board et al., 2004).
CLONING
As part of an effort to produce a transcript map of the Xq28 chromosomal region, Rogner et al. (1996) characterized a cDNA that they designated XAP121, or CLIC2. Heiss and Poustka (1997) reported that the predicted 243-amino acid CLIC2 protein shares 60% identity with the CLIC1 protein, a nuclear chloride channel. Using RT-PCR, Rogner et al. (1996) found that CLIC2 is expressed in fetal liver and adult skeletal muscle. No signal was detected on Northern blots. Board et al. (2004) stated that the predicted CLIC2 protein has a molecular mass of 27.8 kD. The protein sequence showed 58.8% identity to CLIC1 and 18.6% identity to GSTO1. Northern blot analysis detected 2 abundant mRNA species of 1.45 and 2.37 kb, and a third less abundant species of 0.8 kb. The 2 larger mRNA transcripts were widely distributed in human tissues, with highest expression in lung and spleen and lesser expression in heart, liver, and skeletal muscle. Using RT-PCR, Takano et al. (2012) found expression of the CLIC2 gene in all fetal tissues, including brain.
GENE STRUCTURE
Heiss and Poustka (1997) found that the CLIC2 gene contains 6 exons.
MAPPING
Rogner et al. (1996) identified the CLIC2 gene on chromosome Xq28.
GENE FUNCTION
Board et al. (2004) demonstrated that CLIC2 is a strong inhibitor of the cardiac ryanodine receptor (RYR2) calcium release channels in both lipid bilayers and in cardiac sarcoplasmic reticulum vesicles, suggesting that it contributes to intracellular calcium homeostasis by regulating its release from internal stores in the cell. Dulhunty et al. (2005) demonstrated that CLIC2 reduces activation of the RYR2 channel by its primary endogenous ligands ATP and calcium. When CLIC2 was added to the cytoplasmic side of RYR2 channels in lipid bilayers, RYR2 activity was depressed in a reversible, voltage-independent manner. The authors concluded that CLIC2 may act physiologically as a cytosolic inhibitor of RYR2 channels during diastole and during stress.
MOLECULAR GENETICS
In 2 brothers (family K8015) with syndromic X-linked mental retardation-32 (MRXS32;
300886), Takano et al. (2012) identified a hemizygous mutation in the CLIC2 gene (H101Q;
300138.0001). The mutation was inherited from the mother who was thought by family members to have a learning disability. The mutant protein had increased thermal stability compared to wildtype, and caused an increase in both the skeletal RYR1 (
180901) and cardiac RYR2 channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with exces ...
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Oct. 19, 2018: Protein entry updated
Automatic update: OMIM entry 300138 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).