E3 ubiquitin-protein ligase UBR4 (UBR4)

The protein contains 5183 amino acids for an estimated molecular weight of 573841 Da.

 

E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Together with clathrin, forms meshwork structures involved in membrane morphogenesis and cytoskeletal organization. Regulates integrin-mediated signaling. May play a role in activation of FAK in response to cell-matrix interactions. Mediates ubiquitination of ACLY, leading to its subsequent degradation. (updated: March 4, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. 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.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

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.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

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.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology.


Interpro domains
Total structural coverage: 4%
Model score: 0
No model available.

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VariantDescription
dbSNP:rs16862578
a breast cancer sample
dbSNP:rs12584
a melanoma patient
dbSNP:rs2274010

The reference OMIM entry for this protein is 609890

Ubiquitin protein ligase e3 component n-recognin 4; ubr4
Retinoblastoma-associated factor 600; rbaf600
Kiaa1307
P600

CLONING

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned RBAF600, which they designated KIAA1307. RT-PCR ELISA detected BBAF600 in all adult and fetal tissues and specific brain regions examined. Highest expression was in cerebellum and caudate nucleus. By mass spectrometric analysis of proteins associated with retinoblastoma protein (RB1; 614041) in HeLa cells, followed by peptide sequencing, EST database analysis, and screening a cDNA library, Nakatani et al. (2005) cloned RBAF600, which they designated p600. The deduced 5,183-amino acid protein has a calculated molecular mass of 573.5 kD. Immunostaining of human foreskin fibroblasts localized p600 in a continuous meshwork pattern from the nucleus to the cytoplasm, passing through the nuclear envelope. In the cytoplasm, p600 was concentrated at the leading edge of membrane structures.

GENE FUNCTION

The human papillomavirus (HPV) type 16 E7 gene encodes a multifunctional oncoprotein that can subvert multiple cellular regulatory pathways. E7 targets RB and the related pocket proteins p107 (RBL1; 116957) and p130 (RBL2; 180203). By tandem affinity purification in the HPV-positive HeLa cell cervical carcinoma cell line and mass spectrometry, Huh et al. (2005) found that p600 is a cellular target of E7. The association of E7 with p600 was independent of the pocket proteins and was mediated through the N-terminal E7 domain. Huh et al. (2005) observed that depletion of p600 by RNA interference substantially decreased anchorage-independent growth in HPV-positive and -negative human cancer cells. They concluded that p600 is a cellular target of E7 that regulates cellular pathways that contribute to anchorage-independent growth and cellular transformation. Nakatani et al. (2005) found that RBAF600 associates with RB in the nucleus and with Ca(2+)-bound calmodulin (see CALM1, 114180) in the cytoplasm. They noted that in the nucleus, p600 and RB appears to act as a chromatin scaffold, and in the cytoplasm p600 and clathrin (see CLTC, 118955) form a meshwork structure which could contribute to cytoskeletal organization and membrane morphogenesis. Reduced expression of p600 with interfering RNA abrogated integrin (see ITGB1, 135630)-mediated ruffled membrane formation and prevented activation of integrin-mediated survival pathways. Knockdown of p600 sensitized cells to apoptosis induced by cell detachment.

MAPPING

By radiation hybrid analysis, Nagase et al. (2000) mapped the RBAF600 gene to chromosome 1. Gross (2014) mapped the UBR4 gene to chromosome 1p36.13 based on an alignment of the UBR4 sequence (GenBank GENBANK AF348492) with the genomic sequence (GRCh38).

MOLECULAR GENETICS

For discussion of a possible association between variation in the UBR4 gene and episodic ataxia-8 (EA8; 616055), see 609890.0001. ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 609890 was added.