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HGNC Approved Gene Symbol: CHN2
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38): 7:29,146,591-29,514,328 (from NCBI)
The Rho family of GTP-binding proteins is believed to play a role in membrane/cytoskeletal reorganization events. These proteins cycle between active GTP-bound and inactive GDP-bound forms. Activation to the GTP-bound state is mediated by specific guanine nucleotide dissociation stimulators, whereas acceleration of GTP hydrolysis can be accomplished by GTPase-activating proteins (GAPs). Leung et al. (1993) isolated a rat testis cDNA that encodes a 30-kD GAP, which they named beta-chimerin, or beta-1-chimerin. The 1.35-kb beta-1-chimerin transcript is present exclusively in testicular germ cells. The beta-1-chimerin protein contains a phorbol ester-binding region and a GAP domain, and is selective for Rac (see RAC1; 602048).
Leung et al. (1994) detected a 46-kD RacGAP in soluble rat cerebellar extracts, using antibodies against beta-1-chimerin. By screening a human cerebellar cDNA library with a rat beta-1-chimerin cDNA, they cloned a 2.45-kb cDNA corresponding to the cerebellar chimerin, which they named beta-2-chimerin. The encoded 466-amino acid beta-2-chimerin protein is identical to beta-1-chimerin in both the phorbol ester-binding and GAP domains, but it contains an additional N-terminal SH2 domain which is strikingly similar to that of alpha-2-chimerin (CHN1; 118423). Based on Southern blot and cDNA analyses, the authors concluded that beta-1- and beta-2-chimerin are derived from the same gene by alternative splicing. In situ hybridization of rat brain showed that beta-2-chimerin mRNA is expressed only in the cerebellum, mainly in granule cells. Beta-2-chimerin protein is enriched in the particulate/synaptosomal fractions of rat cerebellum.
Yuan et al. (1995) found that beta-2-chimerin is expressed in a variety of human tissues, with the highest expression levels in brain and pancreas. RNase protection assays indicated that beta-2-chimerin expression is downregulated in high-grade gliomas compared to normal brain and low-grade astrocytomas.
Signaling in response to the second messenger diacylglycerol (DAG) is thought to proceed through the activation of protein kinase C (PKC) isozymes. Binding of this lipid second messenger and its related analogs, the phorbol esters, occurs at the C1 domains (also called cysteine-rich regions or zinc fingers) present in PKCs. The phorbol ester receptor family was expanded with the discovery of the chimerins. The several chimerin isoforms each possess a single C1 domain with approximately 40% homology to those present in PKCs. Having previously demonstrated that beta-2-chimerin binds phorbol esters with high affinity, Caloca et al. (1999) analyzed its properties as a DAG receptor by using a series of conformationally constrained cyclic DAG analogs (DAG lactones) as probes. They identified analogs that bind to beta-2-chimerin with high affinity. Cellular studies revealed that these DAG analogs induced translocation of beta-2-chimerin from cytosolic (soluble) to particulate fractions, and specifically to the perinuclear region. Binding and translocation were prevented by mutation of the conserved cys246 in the C1 domain. The results demonstrated that beta-2-chimerin is indeed a high affinity receptor for DAG through binding to its C1 domain and supported the concept that multiple pathways transduce signaling through DAG and the phorbol esters.
Canagarajah et al. (2004) reported the crystal structure at 3.2-angstrom resolution of beta-2 chimerin in its inactive conformation. The structure showed that in the inactive state, the N terminus of beta-2 chimerin protrudes into the active site of the RacGAP domain, sterically blocking Rac binding. The diacylglycerol and phospholipid membrane binding site on the C1 domain is buried by contacts with the 4 different regions of beta-2 chimerin: the N terminus, SH2 domain, RacGAP domain, and the linker between the SH2 and C1 domains. Phospholipid binding to the C1 domain triggers the cooperative dissociation of these interactions, allowing the N terminus to move out of the active site and thereby activating the enzyme.
By fluorescence in situ hybridization, Yuan et al. (1995) mapped the human CHN2 gene to 7p15.3.
Caloca, M. J., Garcia-Bermejo, M. L., Blumberg, P. M., Lewin, N. E., Kremmer, E., Mischak, H., Wang, S., Nacro, K., Bienfait, B., Marquez, V. E., Kazanietz, M. G. Beta-2-chimaerin is a novel target for diacylglycerol: binding properties and changes in subcellular localization mediated by ligand binding to its C1 domain. Proc. Nat. Acad. Sci. 96: 11854-11859, 1999. [PubMed: 10518540] [Full Text: https://doi.org/10.1073/pnas.96.21.11854]
Canagarajah, B., Leskow, F. C., Ho, J. Y. S., Mischak, H., Saidi, L. F., Kazanietz, M. G., Hurley, J. H. Structural mechanism for lipid activation of the Rac-specific GAP, beta-2-chimaerin. Cell 119: 407-418, 2004. [PubMed: 15507211] [Full Text: https://doi.org/10.1016/j.cell.2004.10.012]
Leung, T., How, B.-E., Manser, E., Lim, L. Germ cell beta-chimaerin, a new GTPase-activating protein for p21rac, is specifically expressed during the acrosomal assembly stage in rat testis. J. Biol. Chem. 268: 3813-3816, 1993. [PubMed: 8440677]
Leung, T., How, B.-E., Manser, E., Lim, L. Cerebellar beta-2-chimaerin, a GTPase-activating protein for p21 Ras-related Rac is specifically expressed in granule cells and has a unique N-terminal SH2 domain J. Biol. Chem. 269: 12888-12892, 1994. [PubMed: 8175705]
Yuan, S., Miller, D. W., Barnett, G. H., Hahn, J. F., Williams, B. R. Identification and characterization of human beta 2-chimaerin: association with malignant transformation in astrocytoma. Cancer Res. 55: 3456-3461, 1995. [PubMed: 7614486]