ABCA4
三磷酸腺苷結合盒亞家族A成員4（英語：ATP-binding cassette, sub-family A, member 4），也稱為ABCA4或ABCR，是一種在人類中由ABCA4基因編碼的蛋白質。[6][7][8]
ABCA4是ATP結合盒轉運蛋白（ABC）基因亞家族A的成員，僅存在於多細胞真核生物中。[6]該基因於1997年首次被克隆並鑑定為導致斯特格氏病的基因，斯特格氏病是一種導致黃斑變性的常染色體隱性遺傳病。[9]ABCA4基因轉錄具有兩個跨膜結構域（TMD）、兩個糖基化細胞外結構域（ECD）和兩個核苷酸結合結構域（NBD）的大型視網膜特異性蛋白。ABCA4蛋白幾乎只在視網膜中表達，定位於視桿細胞的外段圓盤邊緣。[10]
結構
以前稱為光感受器邊緣蛋白RmP或ABCA4，最近提出的ABCA4結構由兩個跨膜結構域（TMD）、兩個大的糖基化胞外結構域（ECD）和兩個內部核苷酸結合結構域（NBD）組成。一個TMD跨越膜，六個蛋白質單元連接在一起形成一個結構域。因TMD作為通道或配體結合控制器的特異性和多樣性，所以其通常在基因組中不保守。然而，NBD在不同基因組中高度保守，這一觀察結果與其結合和水解三磷酸腺苷一致。NBD與三磷酸腺苷分子結合，利用高能無機磷酸鹽來改變ABC轉運蛋白的構象。轉錄的ABCA4形成異二聚體：通道的兩個二聚體隔室彼此不同。當TMD位於膜中時，它們形成桶狀結構，可滲透視黃醇配體並控制通道進入其結合位點。[11]一旦三磷酸腺苷在通道的NBD處水解，NBD就會聚集在一起以傾斜和修飾TMD以調節配體與通道的結合。[12]最近提出的類視黃醇轉移模型是由於外部和內部TMD配體結合位點的交替暴露而發生的，所有這些都由三磷酸腺苷的結合控制，是基於最近對細菌ABC轉運蛋白的結構分析。
功能
ABCA4局限於杆和錐的外段盤邊緣。ABCA4的表達比視紫紅質少得多，大約為1:120。哺乳動物ABCA4與其他ABC的比較、ABCA4的細胞定位以及ABCA4基因敲除小鼠的分析表明ABCA4可能作為一種內向的類視黃醇翻轉酶發揮作用。[13]翻轉酶是一種跨膜蛋白，可「翻轉」其構象以跨膜運輸物質。在ABCA4的情況下，翻轉酶促進N-視黃基-磷脂酰乙醇胺（NR-PE）的轉移，NR-PE是全反式視黃醛（ATR）與磷脂酰乙醇胺（PE）的共價加合物，作為帶電物質被困在圓盤內，進入細胞質表面。[14]一旦運輸，ATR被還原為維他命A，然後轉移到視網膜色素上皮，再循環成11-順式視黃醛。這種ABCA4的交替訪問-釋放模型有四個步驟：(1)三磷酸腺苷與NBD的結合，將兩個NBD結合在一起，並暴露位於TMD的外前庭高親和力結合位點，(2)NR-PE/ATR在細胞外的結合通道一側，(3)三磷酸腺苷水解促進門打開和NR-PE/ATR跨膜移動到TMD細胞內部分的低親和力結合位點，以及(4)二磷酸腺苷和無機磷酸鹽（Pi）釋放結合的配體。然後通道準備好再次傳輸另一個NR-PE/ATR分子。
ABCA4-/-基因敲除小鼠已延遲暗適應，但相對於對照組而言，最終杆狀細胞閾值正常。[13]這表明從細胞外膜去除ATR/NR-PE的大量跨膜擴散途徑。用強光漂白視網膜後，ATR/NR-PE在外節顯着積累。這種積累導致形成有毒的陽離子雙吡啶鹽、N-亞視黃基-N-視黃基乙醇胺（A2E），從而導致人類乾性和濕性年齡相關性黃斑變性。[15]從這個實驗中，可以得出結論ABCA4在清除ATR/NR-PE的積累方面具有重要作用，以防止在漂白劑恢復過程中在細胞外感光器表面形成A2E。
臨床意義
已知ABCA4基因的突變會導致常染色體隱性遺傳病斯特格氏黃斑營養不良（STGD），這是一種遺傳性青少年黃斑變性病，會導致感光細胞逐漸喪失。STGD的特徵是視力和色覺降低、中央（黃斑）視力喪失、暗適應延遲以及自體熒光RPE脂褐素積累。[16]去除NR-PE/ATR似乎對正常的漂白劑恢復和減輕導致光感受器退化的持久性視蛋白信號具有重要意義。ABCA4還減輕了ATR積累的長期影響，導致不可逆的ATR與第二個ATR分子和NR-PE結合形成二氫-N-亞視黃基-N-視黃基-磷脂酰-乙醇胺（A2PE-H2）。A2PE-H2捕獲ATR並在外部片段中積累，以進一步氧化成N-亞視黃基-N-視黃基-磷脂酰-乙醇胺（A2PE）。在RPE細胞晝夜盤脫落和吞噬外節後，A2PE在RPE吞噬溶酶體內水解形成A2E。[16]A2E的積累會導致原發性RPE水平的毒性和黃斑變性中的繼發性光感受器破壞。
可能與ABCA4突變相關的其他疾病包括視錐細胞營養不良、視網膜色素變性和年齡相關性黃斑變性。
GENEVA Cleft Consortium研究首先確定ABCA4與唇裂和/或齶裂有關，並通過多個標記提供了全基因組顯着性水平的連鎖和關聯證據。[17]儘管該基因中的SNP與唇裂/齶裂有關，但沒有功能或表達數據支持它作為致病基因，相反，它可能位於與ABCA4相鄰的區域。[18]全基因組關聯、罕見編碼序列變異、顱面特異性表達以及與 IRF6 的相互作用的組合支持相鄰的ARHGAP29基因可能是在非綜合症性唇裂和/或齶裂中發揮作用的致病基因。[19]
參見
參考資料
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