Sakamoto Mika, Suzuki Hirofumi, Yura Kei
Graduate School of Humanities and Sciences, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan.
School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-0072, Japan.
Biophys Physicobiol. 2019 Feb 15;16:68-79. doi: 10.2142/biophysico.16.0_68. eCollection 2019.
Transport of small molecules across the cell membrane is a crucial biological mechanism for the maintenance of the cell activity. ABC transporter family is a huge group in the transporter membrane proteins and actively transports the substrates using the energy derived from ATP hydrolysis. In humans, there are 48 distinct genes for ABC transporters. A variation of a single amino acid in the amino acid sequence of ABC transporter has been known to be linked with certain disease. The mechanism of the onset of the disease by the variation is, however, still unclear. Recent progress in the method to measure the structures of huge membrane proteins has enabled determination of the 3D structures of ABC transporters and the accumulation of coordinate data of ABC transporter has enabled us to obtain clues for the onset of the disease caused by a single variation of amino acid residue. We compared the structures of ABC transporter in apo and ATP-binding forms and found a possible conformation shift around pivot-like residues in the transmembrane domains. When this conformation change in ABC transporter and the location of pathogenic variation were compared, we found a reasonable match between the two, explaining the onset of the disease by the variation. They likely cause impairment of the pivot-like movement, weakening of ATP binding and weakening of membrane surface interactions. These findings will give a new interpretation of the variations on ABC transporter genes and pave a way to analyse the effect of variation on protein structure and function.
小分子跨细胞膜的转运是维持细胞活性的关键生物学机制。ABC转运蛋白家族是转运膜蛋白中的一个庞大群体，它利用ATP水解产生的能量主动转运底物。在人类中，ABC转运蛋白有48个不同的基因。已知ABC转运蛋白氨基酸序列中的单个氨基酸变异与某些疾病有关。然而，这种变异导致疾病发生的机制仍不清楚。测量巨大膜蛋白结构的方法最近取得的进展使得能够确定ABC转运蛋白的三维结构，并且ABC转运蛋白坐标数据的积累使我们能够获得由单个氨基酸残基变异引起疾病的发病线索。我们比较了ABC转运蛋白在无配体和ATP结合形式下的结构，发现在跨膜结构域中围绕类似枢轴的残基可能存在构象变化。当比较ABC转运蛋白的这种构象变化和致病变异的位置时，我们发现两者之间存在合理的匹配，解释了变异导致疾病的发生。它们可能导致类似枢轴运动的受损、ATP结合的减弱以及膜表面相互作用的减弱。这些发现将为ABC转运蛋白基因变异提供新的解释，并为分析变异对蛋白质结构和功能的影响铺平道路。
