Abstract:
Human ATP-binding cassette transporter C11 (ABCC11) is a membrane protein exhibiting ATP-dependent transport activity for a variety of lipophilic anions including endogenous substances and xenobiotics such as anti-cancer agents. Accumulating evidence indicates that ABCC11 wild type is responsible for the high-secretion phenotypes in human apocrine glands including wet type of earwax and the risk of axillary osmidrosis. Also, a less-functional variant of ABCC11 was reportedly associated with a risk for drug-induced toxicity in humans. Thus, functional change in ABCC11 may affect individual\'s constitution and drug toxicity, which led us to reason that functional validation of genetic variations in ABCC11 should be of importance. Therefore, in addition to p.G180R (a well-characterized non-functional variant of ABCC11), we studied cellular expression and function of 10 variants of ABCC11. In this study, ABCC11 function was evaluated as an ATP-dependent transport of radio labeled-dehydroepiandrosterone sulfate using ABCC11-expressing plasma membrane vesicles. Except for p.G180R, other 10 variants were maturated as an N-linked glycoprotein and expressed on the plasma membrane. We found that six variants impaired the net cellular function of ABCC11. Among them, p.R630W was most influential. Including this identification of a significantly-dysfunctional variant, our findings will extend our understanding of genetic variations and biochemical features of ABCC11 protein.
摘要:
人ATP结合盒转运蛋白C11(ABCC11)是对多种亲脂性阴离子(包括内源性物质和异种物质如抗癌剂)表现出ATP依赖性转运活性的膜蛋白。越来越多的证据表明,ABCC11野生型是人类大汗腺高分泌表型的原因,包括湿型耳垢和腋臭的风险。此外,据报道,ABCC11的功能较低的变异体与人类药物诱导的毒性风险相关.因此,ABCC11的功能变化可能会影响个体的体质和药物毒性,这导致我们认为ABCC11遗传变异的功能验证应该很重要。因此,除了p.G180R(ABCC11的特征明确的非功能性变体),我们研究了ABCC11的10种变体的细胞表达和功能。在这项研究中,使用表达ABCC11的质膜囊泡,将ABCC11功能评估为放射性标记的脱氢表雄酮硫酸盐的ATP依赖性转运。除了p.G180R,其他10种变体成熟为N-连接糖蛋白并在质膜上表达。我们发现六种变体损害了ABCC11的净细胞功能。其中,p.R630W最具影响力。包括对功能明显失调的变体的识别,我们的发现将扩展我们对ABCC11蛋白的遗传变异和生化特征的理解.