ATP-binding cassette sub-family C member 4 (ABCC4)

The protein contains 1325 amino acids for an estimated molecular weight of 149527 Da.

 

ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12883481, PubMed:12523936, PubMed:12835412, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12883481, PubMed:12523936, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:18300232, PubMed:17344354). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685). (updated: April 7, 2021)

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, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.


Interpro domains
Total structural coverage: 30%
Model score: 0
No model available.

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VariantDescription
dbSNP:rs11568681
dbSNP:rs11568689
dbSNP:rs4148460
dbSNP:rs45454092
Transport properties comparable to wild-type
dbSNP:rs11568684
Transport properties comparable to wild-type
dbSNP:rs11568701
dbSNP:rs11568705
Transport properties comparable to wild-type
dbSNP:rs11568669
40% reduced expression level compared to wild-type
dbSNP:rs11568699
dbSNP:rs11568697
dbSNP:rs9282570
10% reduced expression level compared to wild-type
20% reduced expression level compared to wild-type
Transport properties comparable to wild-type
Transport properties comparable to wild-type
dbSNP:rs45477596
Transport properties comparable to wild-type
dbSNP:rs45504892
10% reduced expression level compared to wild-type

The reference OMIM entry for this protein is 605250

Atp-binding cassette, subfamily c, member 4; abcc4
Multidrug resistance-associated protein 4; mrp4
Multispecific organic anion transporter b; moatb

DESCRIPTION

ABCC4, also known as MRP4, belongs to a large family of transmembrane proteins involved in active transport of substrates out of cells. ABCC4 acts as an independent regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus (Sassi et al., 2008).

CLONING

By EST database searching with N-terminal PGY1 (ABCB1; 171050) and CFTR (602421) as probes, Allikmets et al. (1996) isolated 21 cDNAs, including a cDNA encoding a 65-amino acid fragment of ABCC4. Using a similar strategy with C-terminal MRP1 (ABCC1; 158343) and CMOAT (ABCC2; 601107) as probes, Kool et al. (1997) obtained cDNAs encoding the C-terminal portion of MRP3 (ABCC3; 604323), ABCC4, and MRP5 (ABCC5; 605251). By degenerative PCR based on the N-terminal sequences of MRP1, followed by plaque hybridization of breast and ovarian bacteriophage libraries, Lee et al. (1998) obtained a cDNA encoding ABCC4, which they termed MOATB. Sequence analysis predicted that the 1,325-amino acid protein, like other ABC transporters, contains nucleotide-binding folds and 12 transmembrane-spanning helices in 2 hydrophobic domains. Northern blot analysis revealed ubiquitous expression of an approximately 6.0-kb transcript that is highest in prostate and lowest in liver and peripheral blood leukocytes (Lee et al., 1998). RNase protection analysis showed only low level expression in a few tissues (Kool et al., 1997). Unlike ABCC2, which is overexpressed in several multidrug-resistant cell lines, ABCC3 and ABCC5 are overexpressed in only a few such cell lines, and ABCC4 is overexpressed in none (Kool et al., 1997). Lamba et al. (2003) isolated an ABCC4 cDNA encoding a nonfunctional protein due to an insertion. The insertion was attributed to 2 additional exons, designated 1a and 1b, that produced premature termination codons (PTCs). A comparison of human, monkey, and rodent ABCC4 genes revealed that these same PTC-producing exons were also highly conserved in evolution. In vitro inhibition of protein synthesis (using puromycin or anisomycin) selectively reduced nonsense-mediated mRNA decay of PTC-containing ABCC4 transcripts in all cell lines tested. Lamba et al. (2003) concluded that the highly conserved PTC-containing exons of the ABCC4 gene may dictate its expression.

GENE FUNCTION

Schuetz et al. (1999) found that MRP4 confers resistance to acyclic nucleoside monophosphates, such as 9-(2-phosphonylmethoxyethyl)guanine (PMEG), and to the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Chen and Klaassen (2004) found that expression of rat Mrp4 mRNA in liver or kidney was not readily induced by several classes of prototypical microsomal enzyme inducers. However, it was induced by a limited number of electrophile response element activators. Sassi et al. (2008) found that expression of MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery smooth muscle cells and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to cAMP-dependent PKA (see 176911) activation and CREB (123810) phosphorylation. Sassi et al. (2008) concluded that MRP4 regulates intracellular cyclic nucleotide levels and mediates cAMP-dependent signal tran ... More on the omim web site

Subscribe to this protein entry history

April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

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 605250 was added.