The reference OMIM entry for this protein is 607207

Stip1 homologous and u box-containing protein 1; stub1
C terminus of hsc70-interacting protein; chip

DESCRIPTION

STUB1, or CHIP, is a ubiquitin ligase/cochaperone that participates in protein quality control by targeting a broad range of chaperone protein substrates for degradation (Min et al., 2008).

CLONING

In a search for tetratricopeptide repeat (TPR)-containing proteins, Ballinger et al. (1999) isolated a cDNA encoding STUB1, which they termed CHIP, from a heart cDNA library. The deduced 303-amino acid protein has a molecular mass of 35 kD and contains three 34-amino acid TPR domains at its N terminus, a central domain rich in charged residues, and 2 potential nuclear localization signals. The N terminus shares similarity with several TPR-containing proteins, particularly those that interact with members of the heat-shock protein family. Human CHIP shares 97% and 53% amino acid identity with its mouse and Drosophila homologs, respectively, with the highest conservation in the 94 residues of the C terminus. Northern blot analysis detected a 1.3-kb transcript at highest levels in striated muscle (heart and skeletal muscle), with lower expression in pancreas and brain, and relatively little expression in lung, liver, placenta, and kidney. Expression of CHIP was readily detected in most cell lines and primary culture cells tested, the exceptions being cells of hematopoietic origin and undifferentiated neuronal cells. Transient transfection experiments in COS-7 cells localized CHIP expression to the cytoplasm. In mouse brain, Shi et al. (2013) found expression of the Stub1 gene in the cerebellum, pons, medulla oblongata, hippocampus, and cerebral cortex. The protein was present in Purkinje cells and colocalized with the glutamate receptor subunit Grin2a (138253) in the cerebellum, pons, and medulla oblongata. Coexpression of Stub1 and Fbx2 (607112) increased the degradation of Grin2a. Shi et al. (2014) found expression of STUB1 in human brain, including within Purkinje cells in the molecular and granular regions of the cerebellum.

GENE FUNCTION

Using a yeast 2-hybrid screen, Ballinger et al. (1999) identified HSC70 (600816) and HSP70 (140550) as potential interaction partners for CHIP. In vitro binding assays demonstrated direct interactions between CHIP and both HSC70 and HSP70, and complexes containing CHIP and HSC70 were identified in immunoprecipitates of human skeletal muscle cells in vivo. CHIP interacted with the C-terminal residues 540 to 650 of HSC70, whereas HSC70 interacted with the N-terminal residues 1 to 197 of CHIP, which contain the TPR domain and the adjacent charged domain. Recombinant CHIP inhibited HSP40 (see 604572)-stimulated ATPase activity of HSC70 and HSP70, suggesting that CHIP blocks the forward reaction of the HSC70-HSP70 substrate-binding cycle. Both luciferase refolding and substrate binding in the presence of HSP40 and HSP70 were inhibited by CHIP. These results indicated that CHIP decreases net ATPase activity and reduces chaperone efficiency, and they implicated CHIP in the negative regulation of the forward reaction of the HSC70-HSP70 substrate-binding cycle. Using an in vitro ubiquitylation assay with recombinant proteins, Jiang et al. (2001) demonstrated that CHIP possesses intrinsic E3 ubiquitin ligase activity and promotes ubiquitylation. This activity was dependent on the C-terminal U box, a domain that shares similarity with yeast UFD2 (603753). CHIP interacted functionally and physically with the stress-responsive ubiquitin-conjugating enzyme family UBCH5 (602961 ... More on the omim web site

Subscribe to this protein entry history

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 607207 was added.

Feb. 23, 2019: Protein entry updated
Automatic update: comparative model was added.

Feb. 23, 2019: Protein entry updated
Automatic update: model status changed

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).