UBOX1, U-boxin omaava E4 ubikitiiniligaasi (16p13.3) ,E4 ubikitiiniligaasi"

Kertaan  E3 ubikitiiniligaasien alaryhmiä.  tämä onkin erikoinen  ubikitiiniligaasi. tätä on sanottu jopa E4 ubikitiiniligaasiksi, koska se järjestää  ja koordinoi,  E1- ubikitiinin aktivoijan, E2- siirtäjän - ja E3 ubikitiiniligaasin, jotta polyubikitiiniä voi siirtää kohdeproteiineille.

 Dimerisoitumismekanismi poikkeaa  yleensä symmetrisestä homodimerisoitumissta  asymmetrisyytensä  takia.  Tämän geenin mutaatio assoioituu spinocerebellaariseen ataxiaan ja  multisysteemineurodegeneraatioon.   Geeni  ilmenee rasvakudoksessa  ja munuaisessa   eniten.

E4 U-BOX ubikitiiniligaaseja , jotkä  koordinoivat  E1, E2 ja E3  entsyymejä polyubikitiinin käsitelyssä on ainakin seuraavat.
1)   UBOX1 STUB1, CHIP; SCAR, HSPABP2, NY-CO-7, SDCCAGT

(2) E4A, UBOX2 , UFD2
(3) E4B, UBOX3, HDNB1, UFD2A

https://flybase.org/reports/FBgg0000203.html

https://www.ncbi.nlm.nih.gov/gene/10273

(16p13.3) STUB1, UBOX1

STIP1 homology and U-box containing protein 1 [ Homo sapiens (human) ]

Gene ID: 10273, updated on 23-Apr-2019

Also known as

CHIP; SCA48; UBOX1; SCAR16; HSPABP2; NY-CO-7; SDCCAG7

Summary

This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2. [provided by RefSeq, Jun 2014]

Expression

Ubiquitous expression in fat (RPKM 42.9), kidney (RPKM 39.1) and 25 other tissues See more

Orthologs

mouse all

Preferred Names

E3 ubiquitin-protein ligase CHIP

Names

CLL-associated antigen KW-8

RING-type E3 ubiquitin transferase CHIP

STIP1 homology and U-box containing protein 1, E3 ubiquitin protein ligase

antigen NY-CO-7

carboxy terminus of Hsp70-interacting protein

heat shock protein A binding protein 2 (c-terminal)

serologically defined colon cancer antigen 7

Conserved Domains (3) summary

sd00006
Location:21 → 51

TPR; TPR repeat [structural motif]

pfam12895
Location:3 → 48

ANAPC3; Anaphase-promoting complex, cyclosome, subunit 3

cd16654
Location:155 → 221

RING-Ubox_CHIP; U-box domain, a modified RING finger, found in carboxyl terminus of HSP70-interacting protein (CHIP) and similar proteins

Related articles in PubMed

1. Symmetry breaking during homodimeric assembly activates an E3 ubiquitin ligase. Ye Z, et al. Sci Rep, 2017 May 11. PMID 28496195, Free PMC Article C-terminus of Hsc/p70-Interacting Protein (CHIP) is a homodimeric E3 ubiquitin ligase. Each CHIP monomer consists of a tetratricopeptide-repeat (TPR), helix-turn-helix (HH), and U-box domain. In contrast to nearly all homodimeric proteins, CHIP is asymmetric. To uncover the origins of asymmetry, we performed molecular dynamics simulations of dimer assembly. We determined that a CHIP monomer is most stable when the HH domain has an extended helix that supports intra-monomer TPR-U-box interaction, blocking the E2-binding surface of the U-box. We also discovered that monomers first dimerize symmetrically through their HH domains, which then triggers U-box dimerization. This brings the extended helices into close proximity, including a repulsive stretch of positively charged residues. Unable to smoothly unwind, this conflict bends the helices until the helix of one protomer breaks to relieve the repulsion. The abrupt snapping of the helix forces the C-terminal residues of the other protomer to disrupt that protomer's TPR-U-box tight binding interface, swiftly exposing and activating one of the E2 binding sites. Mutagenesis and biochemical experiments confirm that C-terminal residues are necessary both to maintain CHIP stability and function. This novel mechanism indicates how a ubiquitin ligase maintains an inactive monomeric form that rapidly activates only after asymmetric assembly.
2. STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. Hayer SN, et al. Orphanet J Rare Dis, 2017 Feb 13. PMID 28193273, Free PMC Article
3. Prognostic value of the ubiquitin ligase carboxyl terminus of the Hsc70-interacting protein in postmenopausal breast cancer. Kurozumi S, et al. Cancer Med, 2016 Aug. PMID 27334118, Free PMC Article
4. CHIP Knockdown Reduced Heat Shock Response and Protein Quality Control Capacity in Lens Epithelial Cells. Zhang W, et al. Curr Mol Med, 2015. PMID 26321754
    Protein quality control (PQC) systems, including molecular chaperones and ubiquitin-proteasome pathway (UPP), plays an important role in maintaining intracellular protein homeostasis. Carboxyl terminus of Hsc70- interacting protein (CHIP) links the chaperone and UPPs, thus contributing to the repair or removal of damaged proteins. Over-expression of CHIP had previously been used to protect cells from environmental stress.
5. Regulation of autophagic flux by CHIP. Guo D, et al. Neurosci Bull, 2015 Aug. PMID 26219223, Free PMC Article

See all (406) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Our results provide the first evidence for a mediator function of cIAP1 and collaborative activity of cIAP1 and CHIP, suggesting that maintaining balanced levels of these E3 ligases might be beneficial for normal cell growth.
2. K6-linked ubiquitylation of FADD by CHIP is a crucial checkpoint in cytokine-dependent extrinsic apoptosis.
3. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level.
4. Data suggest that the molecular basis of genetic defects in CHIP that cause SCAR16 is that most mutations observed in patients with SCAR16 result in destabilization of CHIP leading to down-regulation of it's biquitination function. (SCAR16 = spinocerebellar ataxia autosomal recessive type 16)
5. these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1's cytoprotective effect during staurosporine-induced mammalian cell death.
6. Results identified a new role of CHIP in adipocyte differentiation. CHIP interacts with and mediates the ubiquitylation of PPARgamma , which results in negative effects on adipogenesis.
7. The overexpression of CHIP significantly increased the migration and invasion of the DU145 cells, which is possible due to activation of the AKT signaling pathway and upregulation of vimentin. The expression level of CHIP was observed to be increased in human prostate cancer tissues compared with the adjacent normal tissue.
8. Here the authors show that the mammalian ubiquitin ligase C-terminal Hsp70-interacting protein (CHIP), if freed from chaperones during acute stress, can dock on cellular membranes thus performing a proteostasis sensor function.
9. These results suggest that in the early response to stressful stimuli, MLK4beta-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4beta and MLK3 proteins decline via CHIP-dependent degradation.
10. Prostate cancer cells expressing an S273A mutant of CHIP have attenuated AR degradation upon 2-ME treatment compared with cells expressing wild-type CHIP, supporting the idea that CHIP phosphorylation by Aurora A activates its E3 ligase activity for the AR

Submit: New GeneRIF Correction See all GeneRIFs (153)

Muistiin 20.5. 2019