ABCA4
三磷酸腺苷结合盒亚家族A成员4（英语：ATP-binding cassette, sub-family A, member 4），也称为ABCA4或ABCR，是一种在人类中由ABCA4基因编码的蛋白质。[6][7][8]
ABCA4是ATP结合盒转运蛋白（ABC）基因亚家族A的成员，仅存在于多细胞真核生物中。[6]该基因于1997年首次被克隆并鉴定为导致斯特格氏病的基因，斯特格氏病是一种导致黄斑变性的常染色体隐性遗传病。[9]ABCA4基因转录具有两个跨膜结构域（TMD）、两个糖基化细胞外结构域（ECD）和两个核苷酸结合结构域（NBD）的大型视网膜特异性蛋白。ABCA4蛋白几乎只在视网膜中表达，定位于视杆细胞的外段圆盘边缘。[10]
结构
以前称为光感受器边缘蛋白RmP或ABCA4，最近提出的ABCA4结构由两个跨膜结构域（TMD）、两个大的糖基化胞外结构域（ECD）和两个内部核苷酸结合结构域（NBD）组成。一个TMD跨越膜，六个蛋白质单元连接在一起形成一个结构域。因TMD作为通道或配体结合控制器的特异性和多样性，所以其通常在基因组中不保守。然而，NBD在不同基因组中高度保守，这一观察结果与其结合和水解三磷酸腺苷一致。NBD与三磷酸腺苷分子结合，利用高能无机磷酸盐来改变ABC转运蛋白的构象。转录的ABCA4形成异二聚体：通道的两个二聚体隔室彼此不同。当TMD位于膜中时，它们形成桶状结构，可渗透视黄醇配体并控制通道进入其结合位点。[11]一旦三磷酸腺苷在通道的NBD处水解，NBD就会聚集在一起以倾斜和修饰TMD以调节配体与通道的结合。[12]最近提出的类视黄醇转移模型是由于外部和内部TMD配体结合位点的交替暴露而发生的，所有这些都由三磷酸腺苷的结合控制，是基于最近对细菌ABC转运蛋白的结构分析。
功能
ABCA4局限于杆和锥的外段盘边缘。ABCA4的表达比视紫红质少得多，大约为1:120。哺乳动物ABCA4与其他ABC的比较、ABCA4的细胞定位以及ABCA4基因敲除小鼠的分析表明ABCA4可能作为一种内向的类视黄醇翻转酶发挥作用。[13]翻转酶是一种跨膜蛋白，可“翻转”其构象以跨膜运输物质。在ABCA4的情况下，翻转酶促进N-视黄基-磷脂酰乙醇胺（NR-PE）的转移，NR-PE是全反式视黄醛（ATR）与磷脂酰乙醇胺（PE）的共价加合物，作为带电物质被困在圆盘内，进入细胞质表面。[14]一旦运输，ATR被还原为维生素A，然后转移到视网膜色素上皮，再循环成11-顺式视黄醛。这种ABCA4的交替访问-释放模型有四个步骤：(1)三磷酸腺苷与NBD的结合，将两个NBD结合在一起，并暴露位于TMD的外前庭高亲和力结合位点，(2)NR-PE/ATR在细胞外的结合通道一侧，(3)三磷酸腺苷水解促进门打开和NR-PE/ATR跨膜移动到TMD细胞内部分的低亲和力结合位点，以及(4)二磷酸腺苷和无机磷酸盐（Pi）释放结合的配体。然后通道准备好再次传输另一个NR-PE/ATR分子。
ABCA4-/-基因敲除小鼠已延迟暗适应，但相对于对照组而言，最终杆状细胞阈值正常。[13]这表明从细胞外膜去除ATR/NR-PE的大量跨膜扩散途径。用强光漂白视网膜后，ATR/NR-PE在外节显着积累。这种积累导致形成有毒的阳离子双吡啶盐、N-亚视黄基-N-视黄基乙醇胺（A2E），从而导致人类干性和湿性年龄相关性黄斑变性。[15]从这个实验中，可以得出结论ABCA4在清除ATR/NR-PE的积累方面具有重要作用，以防止在漂白剂恢复过程中在细胞外感光器表面形成A2E。
临床意义
已知ABCA4基因的突变会导致常染色体隐性遗传病斯特格氏黄斑营养不良（STGD），这是一种遗传性青少年黄斑变性病，会导致感光细胞逐渐丧失。STGD的特征是视力和色觉降低、中央（黄斑）视力丧失、暗适应延迟以及自体荧光RPE脂褐素积累。[16]去除NR-PE/ATR似乎对正常的漂白剂恢复和减轻导致光感受器退化的持久性视蛋白信号具有重要意义。ABCA4还减轻了ATR积累的长期影响，导致不可逆的ATR与第二个ATR分子和NR-PE结合形成二氢-N-亚视黄基-N-视黄基-磷脂酰-乙醇胺（A2PE-H2）。A2PE-H2捕获ATR并在外部片段中积累，以进一步氧化成N-亚视黄基-N-视黄基-磷脂酰-乙醇胺（A2PE）。在RPE细胞昼夜盘脱落和吞噬外节后，A2PE在RPE吞噬溶酶体内水解形成A2E。[16]A2E的积累会导致原发性RPE水平的毒性和黄斑变性中的继发性光感受器破坏。
可能与ABCA4突变相关的其他疾病包括视锥细胞营养不良、视网膜色素变性和年龄相关性黄斑变性。
GENEVA Cleft Consortium研究首先确定ABCA4与唇裂和/或腭裂有关，并通过多个标记提供了全基因组显着性水平的连锁和关联证据。[17]尽管该基因中的SNP与唇裂/腭裂有关，但没有功能或表达数据支持它作为致病基因，相反，它可能位于与ABCA4相邻的区域。[18]全基因组关联、罕见编码序列变异、颅面特异性表达以及与 IRF6 的相互作用的组合支持相邻的ARHGAP29基因可能是在非综合征性唇裂和/或腭裂中发挥作用的致病基因。[19]
参见
参考资料
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