組織蛋白酶D
位於11號人類染色體的基因
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是一種天門冬胺酸內切蛋白酶，廣泛分布於溶體中。[8]組織蛋白酶D的主要功能是降解蛋白質並活化溶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
基因
CTSD基因位於11號染色體。
蛋白質
組織蛋白酶D的催化位點包括位於14kDa和34kDa鏈上的兩個關鍵天門冬胺酸殘基（胺基酸33和231）。[12]成熟組織蛋白酶D的最終形式由337個胺基酸殘基、196個重鏈胺基酸殘基和141個輕鏈胺基酸殘基組成。這兩條鏈通過疏水效應連接起來。[13]
功能
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是一種天門冬胺酸蛋白酶，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：隨著pH值的下降，蛋白酶的N端片段會移出活性位點。[15][16][17]與其他天門冬胺酸蛋白酶類似，組織蛋白酶D在活性位點的結合裂隙中容納多達8個胺基酸殘基。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
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 的過表現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基因剔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，這意味著它也可能與動脈粥樣硬化有關。[19][27]
相互作用
參考文獻
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更多閱讀
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