組織蛋白酶D
組織蛋白酶D是一種在人體中由CTSD基因編碼的蛋白質。[6][7]該基因編碼一種溶酶體天門冬胺醯蛋白酶，該蛋白酶由二硫鍵連接的重鏈和輕鏈的蛋白二聚體組成，兩者均由單一蛋白質前體產生。組織蛋白酶D是一種天冬氨酸內切蛋白酶，廣泛分佈於溶酶體中。[8]組織蛋白酶D的主要功能是降解蛋白質並活化溶酶體前區室中生物活性蛋白的前體。[9]這種蛋白酶是肽酶A1家族的成員，具有與胃蛋白酶A相似但比胃蛋白酶A更窄的特異性。 CTSD基因的轉錄從幾個位點開始，包括一個作為雌激素調節轉錄物起始位點的位點。該基因的突變與幾種疾病的發病機制有關，包括乳腺癌和可能的阿茲海默症症。[7]CTSD基因的純合缺失導致出生後階段的早期致死性。[10]據報道，CTSD基因的缺陷是神經元蠟樣脂褐質沉積症（NCL）的根本原因。[11]
結構
[編輯]基因
[編輯]CTSD基因位於11號染色體。
蛋白質
[編輯]組織蛋白酶D的催化位點包括位於14kDa和34kDa鏈上的兩個關鍵天冬氨酸殘基（氨基酸33和231）。[12]成熟組織蛋白酶D的最終形式由337個氨基酸殘基、196個重鏈氨基酸殘基和141個輕鏈氨基酸殘基組成。這兩條鏈通過疏水效應連接起來。[13]
功能
[編輯]在體外，組織蛋白酶D的最適pH值為4.5至5.0。[14]組織蛋白酶D是一種天冬氨酸蛋白酶，它嚴重依賴於其活性位點Asp殘基的質子化。與Asp質子化一起，較低的pH 值也會導致組織蛋白酶D的構象轉換：隨着pH值的下降，蛋白酶的N端片段會移出活性位點。[15][16][17]與其他天冬氨酸蛋白酶類似，組織蛋白酶D在活性位點的結合裂隙中容納多達8個氨基酸殘基。組織蛋白酶D的主要生理功能包括細胞內蛋白質的代謝降解、多肽激素和生長因子的活化和降解、酶前體的活化、酶活化劑和抑制劑的加工、腦抗原加工和細胞程式性死亡的調節。[18][19][20][21]組織蛋白酶D也可以在細胞外空間中找到，[21]它是少數在中性pH條件下顯示出一些活性的組織蛋白酶之一。[22]它能夠活化生長因子VEGF-C和VEGF-D，這可能部分解釋了它與腫瘤進展的相關性。[23]
臨床意義
[編輯]NCL表現為視覺功能的進行性喪失和神經發育衰退、癲癇發作、肌陣攣性抽搐和過早死亡。 CTSD基因是已確定的八個基因之一，其缺陷是導致NCL的原因。[11]據報告，外顯子6中的純合單核苷酸重複可以改變閱讀框並導致255位的過早終止密碼子。組織蛋白酶 D 的過表達刺激致瘤性和轉移以及腫瘤細胞凋亡的開始。這種蛋白酶被認為是乳腺癌預後不良的獨立標誌物，與臨床轉移的發生率相關。[24][25]CTSD基因敲除會導致腸壞死和出血，胸腺凋亡增加，表明某些上皮細胞需要組織蛋白酶D進行組織重塑和更新。[10]另據報告，CTSD基因型可能對男性阿茲海默症風險有強烈影響。[26]組織蛋白酶D的酶活性誘導含有載脂蛋白B-100 的脂蛋白（包括 LDL）的水解修飾，這意味着它也可能與動脈粥樣硬化有關。[19][27]
相互作用
[編輯]參考文獻
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