ABCC6 Membrane Protein Introduction

Introduction of ABCC6

ABCC6, also known as URG7 Protein, ABC34, ARA, GACI2, MLP1, MRP6, PXE1, PXE, URG7, or ATP-binding cassette, subfamily c (cftr/mrp), member 6, is a 165 kDa transmembrane protein that is composed of 1503 amino acids. In humans, it is encoded by the ABCC6 gene mapping at chromosome 16p13.11. This gene has been determined to contain 31 exons and the 5-prime upstream region of it includes a major Alu element of more than 4.5 kb. Later, two pseudogenes are identified with high sequence homology with the 5-prime end of ABCC6 genes. This protein belongs to the superfamily of ATP-binding cassette (ABC) transporters and consists of three transmembrane domains (TMD) involving TMD0, TMD1, and TMD2. Among them, TMD0 is speculated to comprise five transmembrane alpha helices, while TMD1, 2 contains six, respectively.

Function of ABCC6 Membrane Protein

The ABCC6 codes for the multidrug resistance protein 6, which arises in genomes by tandem gene duplication, a process that also generates the ABCC1 gene. In humans, it involves in the prevention of soft tissue calcification, which is a critical physiological mechanism in the skeletal tissue formation, a tightly controlled and restricted event to specific body regions. Some reports suggested that ABCC6 is able to stimulate the release of adenosine triphosphate (ATP) from cells by an unknown mechanism. The ATP is promptly broken down into adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate helps to control the calcification and mineralization in the body. Biallelic inactivating ABCC6 mutations would result in most cases to a rare autosomal recessive genetic disorder, Pseudoxanthoma elasticum (PXE), featured by aberrant mineralization of soft connective tissues, such as eyes, skins, arteries, and retinas. Also, its mutations are linked to several cases of Generalized Arterial Calcification of Infancy (GACI), a calcification disorder that has impacts on circulatory systems and is related to mutations of Ectonucleotide Phosphodiesterase 1 (ENPP1) gene.

Fig.1 Membrane topology, homology model and in vivolocalization of human ABCC6 and its mutants. (Arányi, 2013)

Application of ABCC6 Membrane Protein in Literature

1. Parreira B., et al. Persistence of the ABCC6 genes and the emergence of the bony skeleton in vertebrates. Sci Rep. 2018, 8(1): 6027. PubMed ID: 29662086
   
   

   Six diseases resulting in amino acid mutations in human MRP6 were a normal characteristic of abcc6 in fish, which suggested they did not have a deleterious impact on proteins. After scale removal the abcc6 for 5-10 days and abcc1 for 10 days, the expression of these genes was up-regulated relative to the intact control skin and it was consistent with a time of intense scale mineralization.

2. De Vilder E.Y.G., et al. Pathogenic variants in the abcc6 gene are associated with an increased risk for ischemic stroke. Brain Pathol. 2018. PubMed ID: 29722917
   
   

   Both processes mentioned were induced in ischemia, authors proposed a pro-ischemic state possibly explaining a higher risk to suffer from the ischemic stroke in patients with pathogenic ABCC6 variants, since this could lower the threshold to develop acute ischemic situations in patients. In summary, the heterozygous ABCC6 variant may as a risk factor for ischemic stroke.

3. Eadie L.N., et al. ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells. PLoS One. 2018, 13(1): e0192180. PubMed ID: 29385210
   
   

   Findings indicated that three inhibitors greatly reduced nilotinib IC50 (p<0.001) demonstrating ABCC6 was likely implicated in the nilotinib transport. Cell line data identified these results and similar results were gained for dasatinib, which suggested that nilotinib and dasatinib may be substrates of ABCC6 and it was the first report of ABCC6 involvement in TKI transport.

4. Bertamino M., et al. ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum. Eur J Paediatr Neurol. 2018, 22(4): 725-728. PubMed ID: 29709427
   
   

   This paper reported two children with PXE showing isolated multisystem vasculopathy and early-onset stroke. In a patient, diagnosis was postponed until typical dermatologic alterations present; in another case, next-generation sequencing (NGS) study resulted in the early diagnosis and specific follow-up.

5. Favre G., et al. The ABCC6 transporter: a new player in biomineralization. Int J Mol Sci. 2017, 18(9). PubMed ID: 28891970
   
   

   Pseudoxanthoma elasticum (PXE), an autosomal recessive inheritance, was induced by ABCC6 gene mutations. Several ABC transporters, including ABCC1 or ABCC7 could provide a clear understanding of what ABCC6 exact function was. There also discussed a hypothesis on the possible roles of ABCC6 in certain acquired metabolic diseases.

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Reference

1. Arányi T, et al. (2013). Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations. Front Genet. 4, 27.

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