Chloride intracellular channel protein 2 (CLIC2)
The protein contains 247 amino acids for an estimated molecular weight of 28356 Da.
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)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
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.
This protein is annotated as membranous in Gene Ontology.
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| Variant | Description |
|---|---|
| MRXS32 |
No binding partner found
Biological Process
Chloride transmembrane transport
Glutathione metabolic process
Negative regulation of ryanodine-sensitive calcium-release channel activity
Positive regulation of binding
Regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
Regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
Signal transduction
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 ... More on the omim web site
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).