Soupene Eric, Kemaladewi Dwi Utami, Kuypers Frans A
Children's Hospital Oakland Research Institute, Oakland, CA, USA.
J Receptor Ligand Channel Res. 2008;1:1-10. doi: 10.2147/jrlcr.s3773.
The asymmetric distribution of the amino-containing phospholipids, phosphatidyl-serine (PS) and phosphatidyl-ethanolamine (PE), across the two leaflets of red blood cell (RBC) membrane is essential to the function and survival of the cell. PS and PE are sequestered in the inner leaflet by an ATP-dependent transport activity of a membrane protein known as the RBC flippase that specifically moves amino-phospholipids from the outer to the inner leaflet. The enucleated RBC lacks the means to replace damaged enzymes and inactivation of the flippase can lead to the unwarranted exposure of PS on the cell surface. Loss in the ability to maintain phospholipid asymmetry is exacerbated in RBC disorders and PS-exposing RBCs present in the circulation play a significant role in the pathology of hemoglobinopathies. We identified the Atp8a1 protein, a member of the family of the P(4)-type ATPases, as a RBC flippase candidate. Atp8a1 is expressed in RBC precursors and is present in the membrane of mature red cells. The flippase activity of the protein was established in purified secretory vesicles of Saccharomyces cerevisiae. ATPase activity was stimulated by PS and PE. In addition, Atp8a1 can move PS molecules across the leaflets of the vesicle membrane in presence of ATP.
含氨基磷脂，即磷脂酰丝氨酸（PS）和磷脂酰乙醇胺（PE），在红细胞（RBC）膜的两层之间呈不对称分布，这对细胞的功能和存活至关重要。PS和PE通过一种称为RBC翻转酶的膜蛋白的ATP依赖性转运活性被隔离在内层。该翻转酶能特异性地将氨基磷脂从外层转运至内层。去核的RBC缺乏替换受损酶的途径，翻转酶的失活会导致PS在细胞表面无端暴露。在RBC疾病中，维持磷脂不对称性的能力丧失会加剧，循环中出现的暴露PS的RBC在血红蛋白病的病理过程中起重要作用。我们鉴定出P(4)型ATP酶家族成员Atp8a1蛋白为RBC翻转酶候选物。Atp8a1在RBC前体中表达，并存在于成熟红细胞的膜中。该蛋白的翻转酶活性在酿酒酵母纯化的分泌囊泡中得到证实。ATP酶活性受到PS和PE的刺激。此外，在ATP存在的情况下，Atp8a1可使PS分子穿过囊泡膜的两层。
