胱天蛋白酶9
胱天蛋白酶9（英語：Caspase 9）是人類中由CASP9基因編碼的一種酶。它是一種啟動型胱天蛋白酶，[6]對於許多組織中發現的細胞凋亡途徑至關重要。[7]已經在已知存在的所有哺乳動物中發現了胱天蛋白酶9同源物，如小鼠（Mus musculus）和黑猩猩（Pan troglodytes）。[8]
胱天蛋白酶9屬於胱天蛋白酶家族，主要參與細胞凋亡和細胞因子信號轉導。[9]凋亡信號導致線粒體釋放細胞色素c並活化apaf-1（凋亡複合體），然後將胱天蛋白酶9的酶原裂解為活性二聚體形式。[7]這種酶的調節是通過異構抑制劑的磷酸化來實現的，抑制二聚化並誘導構象變化。[9]
正確的胱天蛋白酶9功能對於細胞凋亡至關重要，有助於中樞神經系統的正常發育。[9]胱天蛋白酶9還具有多種與其在細胞凋亡中的作用無關的附加細胞功能。胱天蛋白酶9的非凋亡作用包括調節程式性壞死、細胞分化、先天免疫反應、感覺神經元成熟、線粒體穩態、皮質脊髓路徑組織和缺血性血管損傷。[10]如果沒有正確的功能，可能導致異常的組織發育，引發功能異常、疾病和過早死亡。[9]胱天蛋白酶9缺失功能突變與免疫缺陷/淋巴增生性障礙、神經管缺陷以及類李-佛美尼綜合症有關。胱天蛋白酶9活性增加與肌萎縮性脊髓側索硬化症、視網膜脫離和慢通道綜合症，以及各種神經、自體免疫和心血管疾病的發展有關。[10]
由於選擇性剪接，產生了不同的胱天蛋白酶9蛋白質亞型。[11]
結構
[編輯]與其他胱天蛋白酶類似，胱天蛋白酶9具有三個結構域：N端前結構域、大亞基和小亞基。[9]端前結構域也稱為長前結構域，其中包含胱天蛋白酶活化結構域（CARD）基序。[12]前結構域通過連接環與催化結構域連接。[13]
胱天蛋白酶9單體由一大一小亞基組成，均包含催化結構域。[14]與其他胱天蛋白酶中通常保守的活性位點基序QACRG不同，胱天蛋白酶9具有基序QACGG。[15][13]
當二聚化時，胱天蛋白酶9在每個二聚體中具有兩種不同的活性位點構象。[14]其中一個位點與其他胱天蛋白酶的催化位點非常相似；而第二個位點沒有「活化環」，會破壞該特定活性位點的催化機制。[14]活性位點周圍的表面環很短，基質結合裂縫更開放，因此產生了廣泛的基質特異性。[16]在胱天蛋白酶9的活性位點內，必須有特定的氨基酸位於正確的位置，才能產生催化活性。位於P1位的氨基酸Asp是必需的，而位於P2位的氨基酸His更受青睞。[17]
定位
[編輯]蛋白質表達
[編輯]人類的胱天蛋白酶9在胎兒和成人組織中表達。[15][13]該酶的組織表達無處不在，在大腦和心臟中表達最高，特別是在成人發育階段的心臟肌肉細胞中。[19]肝臟、胰腺和骨骼肌以中等水平表達該酶，而所有其他組織以低水平表達該酶。[19]
機制
[編輯]活化的胱天蛋白酶9充當啟動型胱天蛋白酶，通過裂解從而活化下游執行型胱天蛋白酶，從而引發細胞凋亡。[20]一旦活化，胱天蛋白酶9就會繼續裂解胱天蛋白酶3、6和7，這些酶會裂解其他細胞靶點而啟動胱天蛋白酶級聯反應。[9]
當胱天蛋白酶9失活時，它以單體形式作為酶原存在於細胞質中。[14][21]然後被apaf-1中的CARD通過識別胱天蛋白酶9中的CARD招募並活化。[22]
加工
[編輯]在活化之前，胱天蛋白酶9必須經過加工處理。[23]最初，胱天蛋白酶9被製成無活性的單鏈酶原。[23]當凋亡複合體與胱天蛋白酶9前體結合時，加工就會發生，因為apaf-1有助於酶原的自蛋白水解加工。[23]加工後的胱天蛋白酶9與凋亡體複合物結合，形成全酶。[24]
活化
[編輯]胱天蛋白酶9二聚化時會發生活化，有兩種不同的方式可以實現：
催化活性
[編輯]胱天蛋白酶9的優選切割序列為Leu-Gly-His-Asp-(cut)-X。[17]
調節
[編輯]胱天蛋白酶9的負調節通過磷酸化發生。[9]這是通過絲氨酸-196上的絲氨酸-蘇氨酸激酶Akt來完成的，它抑制胱天蛋白酶9的活化和蛋白酶活性，從而抑制胱天蛋白酶9及細胞凋亡的進一步活化。[26]Akt充當胱天蛋白酶9的變構抑制劑，因為絲氨酸-196的磷酸化位點離催化位點很遠。[26]該抑制劑影響胱天蛋白酶9的二聚化並引起構象變化，從而影響胱天蛋白酶9的基質結合裂口。[26]
Akt可以在體外作用於加工過的和未加工過的胱天蛋白酶9，其中加工過的胱天蛋白酶9的磷酸化發生在大亞基上。[27]
缺陷和突變
[編輯]缺乏胱天蛋白酶9很大程度上會影響大腦及其發育。[28]與其他胱天蛋白酶相比，這種胱天蛋白酶的突變或缺陷的影響是有害的。[28]在細胞凋亡中，胱天蛋白酶9發揮的起始作用是導致那些患有非典型胱天蛋白酶9的人出現嚴重影響的原因。
胱天蛋白酶9不足的小鼠具有受影響或異常大腦的主要表型。[9]由於細胞凋亡減少而導致大腦變大，從而導致額外神經元的增加，這是在胱天蛋白酶9缺陷小鼠中觀察到的表型的一個例子。[29]那些沒有胱天蛋白酶9的純合子會因大腦發育異常而在圍產期死亡。[9]
在人類中，胱天蛋白酶9的表達因組織而異，並且不同水平具有生理作用。[29]低含量的胱天蛋白酶9會導致癌症和神經退行性疾病如阿茲海默症等。[29]胱天蛋白酶9單核苷酸多態性（SNP）水平和全基因水平的進一步改變可能導致與非霍奇金淋巴瘤相關的生殖系突變。[30]胱天蛋白酶9啟動子中的某些多態性會提高胱天蛋白酶9的表達率，這會增加人患肺癌的風險。[31]
臨床意義
[編輯]胱天蛋白酶9水平或功能異常會影響臨床界。胱天蛋白酶9對大腦的影響可能會引領未來通過靶向治療進行抑制研究，特別是與大腦相關的疾病，因為這種酶可能參與神經元疾病的發展途徑。[9]
胱天蛋白酶的引入也可能具有醫療益處。[20]在移植物對抗宿主疾病的背景下，可以引入胱天蛋白酶9作為誘導開關。[32]當小分子存在時，它會二聚化並引發細胞凋亡，消除淋巴細胞。[32]
iCasp9
[編輯]iCasp9（誘導型胱天蛋白酶9）是一種嵌合抗原受體T細胞（CAR T細胞）的控制系統。CAR T細胞是經過基因改造的T細胞，對腫瘤細胞具有細胞毒性。有證據表明CAR T細胞可有效治療B細胞惡性腫瘤。然而，由於CAR T細胞會產生毒性，因此對細胞及其靶點的用戶控制至關重要。[33]對CAR T細胞進行控制的多種方法之一是通過藥物控制的合成系統。iCasp9是通過修飾胱天蛋白酶9並將其與FK506結合蛋白融合而創建的。[33]iCasp9可以作為誘導性自殺基因添加到CAR T細胞中。[34]
如果CAR T細胞治療導致嚴重副作用，iCasp9可用於停止治療。給予雷帕黴素等小分子藥物會導致藥物與FK506結構域結合。[34]這反過來會誘導胱天蛋白酶9的表達，從而觸發CAR T細胞的細胞死亡。[34]
替代轉錄
[編輯]通過選擇性剪接可產生了四種不同的胱天蛋白酶9變體。
胱天蛋白酶9α（9L）
[編輯]該變體用作參考序列，它具有完整的半胱氨酸蛋白酶活性。[12][35]
胱天蛋白酶9β（9S）
[編輯]異構體2不包括外顯子3、4、5和6，它缺少氨基酸140-289。[12][35]胱天蛋白酶9S沒有中心催化結構域，因此它通過附着在凋亡體上作為胱天蛋白酶9α的抑制劑，抑制胱天蛋白酶級聯和細胞凋亡。[12][36]胱天蛋白酶9β被稱為內源性顯性失活亞型。
胱天蛋白酶9γ
[編輯]該變體缺少氨基酸155-416，並且對於氨基酸152-154，序列AYI更改為TVL。[35]
異構體4
[編輯]與參考序列相比，它缺少氨基酸1-83。[35]
相互作用
[編輯]胱天蛋白酶9已被證明可以與以下物質相互作用：
參見
[編輯]參考文獻
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