CUL-5 (11q22.3) VACM1; CLR- E3 ubikitiiniligaasit)

CLR ubikitiiniligaasit  =  CUL-RING- E3-ubikitiiniligaasit

CUL5 (Kr.11q22.3) ,VACM-1,    E3- ubikitiiniligaasi

Tuumorisuppressorigeeni, Cullin -5 RING E3 ubikitiiniligaasi , (Nedd8 aktivoituva CUl-RING- E 3-ubikitiiniligaasi) 

LÄHDE:

https://www.ncbi.nlm.nih.gov/gene/8065

Also known as CUL-5; VACM1; VACM-1

Expression Ubiquitous expression in thyroid (RPKM 9.9), kidney (RPKM 8.6) and 25 other tissues See more Orthologs mouse all

Preferred Names

cullin-5

Names

Cullin-5 (vasopressin-activated calcium-mobilizing receptor-1)

Vasopressin-activated calcium-mobilizing receptor-1

vasopressin-activated calcium-mobilizing receptor 1

https://www.ncbi.nlm.nih.gov/protein/NP_003469.2

Conserved Domains (2) summary

pfam00888
Location:20 → 671

Cullin; Cullin family

pfam10557
Location:713 → 772

Cullin_Nedd8; Cullin protein neddylation domain This is the neddylation site of cullin proteins which are a family of structurally related proteins containing an evolutionarily conserved cullin domain. With the exception of APC2, each member of the cullin family is modified by Nedd8 and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome recognizes and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chains. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex in Saccharomyces cerevisiae, and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle control and for embryogenesis in metazoans. The only identified Nedd8 substrates are cullins. Neddylation results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue.

Related articles in PubMed

1. CUL5 is required for thalidomide-dependent inhibition of cellular proliferation. Kunkler B, et al. PLoS One, 2018. PMID 29746508, Free PMC Article
2. Cullin 5-RING E3 ubiquitin ligases, new therapeutic targets? Lamsoul I, et al. Biochimie, 2016 Mar. PMID 26253693
3. E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells. Samant RS, et al. Proc Natl Acad Sci U S A, 2014 May 6. PMID 24760825, Free PMC Article
4. Downregulation of miR-7 upregulates Cullin 5 (CUL5) to facilitate G1/S transition in human hepatocellular carcinoma cells. Ma C, et al. IUBMB Life, 2013 Dec. PMID 24339204
5. Mutational analysis of VACM-1/cul5 exons in cancer cell lines. Lewis SP, et al. APMIS, 2011 Jul. PMID 21635549

See all (185) citations in PubMed

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

GeneRIFs: Gene References Into Functions

1. Clinical tissue examination revealed that the co-expression of ERp29 and CUL5 was positive relative to one another, and the clinicopathological data proved that the high expression of ERp29 was associated with metastasis and the poor prognosis of patients with colorectal cancer (CRC). Therefore, ERp29 should accompany CUL5 to support malignancy for endoplasmic reticulum stress cancer cells.
2. CUL5 may be an important part of the mechanism for thalidomide-dependent inhibition.
3. These findings report genetic variants possibly associated with susceptibility to HIV-1 infection (CUL5 rs11212495, rs7103534, rs7117111) and partial viral load control (APOBEC3G rs2294367).
4. structural model suggests that the diverse FIV and HIV-1 Vifs use conserved residues for Cullin 5 binding, FIV Vif binds Cullin 5 independently of zinc, in contrast to HIV-1 Vif.
5. these findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-kappaB
6. CUL5 neddylation may allosterically tune polyubiquitin chain length and topology. Abstract

Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5^CTD) and Rbx1 (Cul5^CTD residues R538/R569 and Rbx1 residue E67, or Cul5^CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.

6. Study found that CUL5 expression was significantly decreased in both endometrioid adenocarcinomas with the more aggressive serous type displaying a higher reduction. Its mRNA and protein overexpression in endometrial cancer cells resulted in decreased cell proliferation.
7. Studies indicate that Cullin-RING E3 ubiquitin ligases (CRL) are key players of the ubiquitylation pathway.
8. These results provide important information on the assembly of the Vif-CUL5-E3 ubiquitin ligase and identify a new viV binding interface with CBF-beta at the C-terminus of HIV-1 Vif.
9. Data indicate that cell surface adhesion molecules VCAM-1 and P-selectin play some roles in mechanical stretch-induced HL-60 cell adhesion to mouse common carotid arteries.

Submit: New GeneRIF Correction See all GeneRIFs (38)

LISÄYS 26.11. 2019.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812663/
( Tämä linkki mainitsee miten CLR-5- välitteisesti voi  virus  aiheuttaa APOBEC proteiinin joutumisen silppuriin.

Abstract

The suppressor of cytokine signaling (SOCS) box consists of the BC box and the cullin 5 (Cul5) box, which interact with Elongin BC and Cul5, respectively. SOCS box-containing proteins have ubiquitin ligase activity mediated by the formation of a complex with the scaffold protein Cul5 and the RING domain protein Rbx2, and are thereby members of the cullin RING ligase superfamily. Cul5-type ubiquitin ligases have a variety of substrates that are targeted for polyubiquitination and proteasomal degradation. Here, we review the current knowledge on the identification of Cul5 and the regulation of its expression, as well as the signaling pathways regulated by Cul5 and how viruses highjack the Cul5 system to overcome antiviral responses.

Keywords: Ubiquitin, Cullin 5, Elongin, CRL complex