ABCC9 Membrane Protein Introduction

Introduction of ABCC9

ABCC9, also known as SUR2, ATFB12, ABC37, CANTU, CMD1O, or ATP-binding cassette, subfamily C (CFTR/MRP), member 9, codes for a polypeptide of 1549 amino acids which is named as sulfonylurea receptor 2 (SUR2). It is a 174.2 kDa membrane protein and in humans located on the chromosome 12p12.1. The protein produces a subunit of a channel that transports potassium ions across cell membranes. Each of the channels is composed of eight subunits, four ABCC9 proteins and four proteins generated from either the KCNJ8 gene or KCNJ11 gene. The subunits of ABCC9 regulate the activity of these channels, deciding whether it is open or closed. Some diseases correlated with ABCC9 are Cantu syndrome and familial atrial fibrillation. And among its associated pathways are inwardly rectifying K+ channels and cardiac conduction.

Function of ABCC9 Membrane Protein

The ABCC9 protein is a member of the multidrug resistance-associated protein (MRP) subfamily, a subunit of the ATP-binding cassette (ABC) transporter superfamily. This protein is thought to constitute ATP-sensitive potassium (K-ATP) channels in cardiac, skeletal, as well as vascular and non-vascular smooth muscle. ABCC9, together with KCNJ11, forms cardiac and smooth muscle-type K-ATP channels. It is required for the activation and regulation of the channel while KCNJ11 makes up the channel pore. The channels open and close are in response to the amount of ATP (the main energy source of cells) inside the cell. The resulting transport of potassium ions is part of a complex network of signals that transmit chemical messages into and out of cells. Based on the protein structure of ABCC9, some reports suggest a role as the drug-binding channel-modulating subunit of the extra-pancreatic K-ATP channels. In addition, since ABCC9 is observed in most human tissues and relevant to many human diseases, it has been considered as a target for therapeutic strategies.

Fig.1 Molecular model of the ABCC9 protein. (Harakalova, 2012)

Application of ABCC9 Membrane Protein in Literature

1. McClenaghan C., et al. Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in K_ATP channel gain-of-function by differential mechanisms. J Biol Chem. 2018, 293(6): 2041-2052. PubMed ID: 29275331
   
   

   This report concluded mutations in CS-related SUR2 resulted in KATP gain-of-function. They contributed to linking CS genotypes to phenotypes and illustrated the underlying molecular mechanisms, such as consequences for inhibitory drug sensitivity and insights that may inform the development of therapeutic methods to manage CS.

2. Katsumata Y., et al. Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B , ABCC9 , and KCNMB2. Neurobiol Aging. 2017, 53: 193.e17-193.e25. PubMed ID: 28131462
   
   

   To investigate more about the genetic risk of hippocampal sclerosis of aging (HS-Aging) pathology, gene-based associations of GRN, TMEM106B, ABCC9, and KCNMB2 genes were tested. The HS-Aging pathology protective ABCC9 haplotype was related to the reduced ABCC9 expression, illustrating a possible toxic gain of function.

3. Kim H., et al. Clinical and Molecular Delineation of a Novel Cys1050Phe Missense Mutation in the ABCC9 Gene in a Korean Patient with Cantú Syndrome. Clin Lab. 2017, 63(5): 991-995. PubMed ID: 28627835
   
   

   Cantú syndrome, as a rare disease, was featured by congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly, and was recognized as a rare syndrome. This paper reported the first case of Cantú syndrome in Korea and correlated changes in overall development with rehabilitation over some months.

4. Afifi H.H., et al. De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder. Pediatr Dermatol. 2016, 33(2): e109-13. PubMed ID: 26871653
   
   

   Here, the patient case mentioned in this study provided further evidence that these syndromes were regarded as an expression of ABCC9-associated disorders, ranging from hypertrichosis as well as acromegaloid facies to a severe end of Cantu syndrome.

5. Nelson P.T., et al. Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging. J Neurochem. 2015, 134(6): 1026-1039. PubMed ID: 26115089
   
   

   ABCC9 genetic polymorphism was related to the increased risk for many human diseases. Here, authors described novel ABCC9 variants in the human brain, corresponding to the altered 3'UTR length, which resulted in targeting by miR-30c. Also, they determined that the HS-Aging risk mutation was correlated with variations in ABCC9 transcript level.

ABCC9 Preparation Options

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Reference

1. Harakalova M, et al. (2012). Dominant missense mutations in ABCC9 cause Cantú syndrome. Nat Genet. 44(7), 793-796.

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