组织蛋白酶D

组织蛋白酶D是一种在人体中由CTSD基因编码的蛋白质。^[6][7]该基因编码一种溶酶体天冬氨酰蛋白酶，该蛋白酶由二硫键连接的重链和轻链的蛋白二聚体组成，两者均由单一蛋白质前体产生。组织蛋白酶D是一种天冬氨酸内切蛋白酶，广泛分布于溶酶体中。^[8]组织蛋白酶D的主要功能是降解蛋白质并激活溶酶体前区室中生物活性蛋白的前体。^[9]这种蛋白酶是肽酶A1家族的成员，具有与胃蛋白酶A相似但比胃蛋白酶A更窄的特异性。 CTSD基因的转录从几个位点开始，包括一个作为雌激素调节转录物起始位点的位点。该基因的突变与几种疾病的发病机制有关，包括乳腺癌和可能的阿茲海默症症。^[7]CTSD基因的纯合缺失导致出生后阶段的早期致死性。^[10]据报道，CTSD基因的缺陷是神经元蜡样脂褐质沉积症（NCL）的根本原因。^[11]

组织蛋白酶D
已知的结构 PDB 直系同源搜索: PDBe RCSB PDBID列表 1LYA、​1LYB、​1LYW、​4OBZ、​4OC6、​4OD9
识别号
别名	CTSD；, CLN10, CPSD, HEL-S-130P, cathepsin D
外部ID	OMIM：116840 MGI：88562 HomoloGene：55616 GeneCards：CTSD
相关疾病
neuronal ceroid lipofuscinosis 10、​神经元蜡样脂褐质储积症[1]
基因位置（人类） 染色体 11号染色体[2] 基因座 11p15.5 起始 1,752,752 bp[2] 终止 1,764,573 bp[2]
基因位置（小鼠） 染色体 小鼠7号染色体[3] 基因座 7|7 F5 起始 141,929,648 bp[3] 终止 141,941,775 bp[3]
RNA表达模式
查阅更多表达数据
基因本体 分子功能 • 肽酶活性 • 水解酶活性 • 血浆蛋白结合 • serine-type endopeptidase activity • cysteine-type endopeptidase activity • aspartic-type endopeptidase activity • aspartic-type peptidase activity 细胞组分 • lysosomal lumen • 外排体 • 脂筏模型 • 细胞外间质 • 溶酶体 • 黑色素体 • 细胞外空间 • specific granule lumen • tertiary granule lumen • ficolin-1-rich granule lumen • 细胞外区域 • collagen-containing extracellular matrix • lysosomal membrane • endosome membrane 生物学过程 • protein catabolic process • 自噬 • collagen catabolic process • antigen processing and presentation of exogenous peptide antigen via MHC class II • 蛋白酶解 • neutrophil degranulation • lipoprotein catabolic process • positive regulation of apoptotic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • regulation of establishment of protein localization Sources:Amigo / QuickGO
直系同源
物种	人类	小鼠
Entrez	1509	13033
Ensembl	ENSG00000117984	ENSMUSG00000007891
UniProt	P07339	P18242
mRNA​序列	NM_001909	NM_009983
蛋白序列	NP_001900	NP_034113
基因位置​（UCSC）	Chr 11: 1.75 – 1.76 Mb	Chr 7: 141.93 – 141.94 Mb
PubMed​查找	[4]	[5]
维基数据
查看/编辑人类 查看/编辑小鼠

结构

基因

CTSD基因位于11号染色体。

蛋白质

组织蛋白酶D的催化位点包括位于14kDa和34kDa链上的两个关键天冬氨酸残基（氨基酸33和231）。^[12]成熟组织蛋白酶D的最终形式由337个氨基酸残基、196个重链氨基酸残基和141个轻链氨基酸残基组成。这两条链通过疏水效应连接起来。^[13]

功能

在体外，组织蛋白酶D的最适pH值为4.5至5.0。^[14]组织蛋白酶D是一种天冬氨酸蛋白酶，它严重依赖于其活性位点Asp残基的质子化。与Asp质子化一起，较低的pH 值也会导致组织蛋白酶D的构象转换：随着pH值的下降，蛋白酶的N端片段会移出活性位点。^[15][16][17]与其他天冬氨酸蛋白酶类似，组织蛋白酶D在活性位点的结合裂隙中容纳多达8个氨基酸残基。组织蛋白酶D的主要生理功能包括细胞内蛋白质的代谢降解、多肽激素和生长因子的激活和降解、酶前体的激活、酶激活剂和抑制剂的加工、脑抗原加工和细胞程序性死亡的调节。^{[18][19][20][21]}组织蛋白酶D也可以在细胞外空间中找到，^[21]它是少数在中性pH条件下显示出一些活性的组织蛋白酶之一。^[22]它能够激活生长因子VEGF-C和VEGF-D，这可能部分解释了它与肿瘤进展的相关性。^[23]

临床意义

NCL表现为视觉功能的进行性丧失和神经发育衰退、癫痫发作、肌阵挛性抽搐和过早死亡。 CTSD基因是已确定的八个基因之一，其缺陷是导致NCL的原因。^[11]据报告，外显子6中的纯合单核苷酸重复可以改变阅读框并导致255位的过早终止密码子。组织蛋白酶 D 的过表达刺激致瘤性和转移以及肿瘤细胞凋亡的开始。这种蛋白酶被认为是乳腺癌预后不良的独立标志物，与临床转移的发生率相关。^[24][25]CTSD基因敲除会导致肠坏死和出血，胸腺凋亡增加，表明某些上皮细胞需要组织蛋白酶D进行组织重塑和更新。^[10]另据报告，CTSD基因型可能对男性阿茲海默症风险有强烈影响。^[26]组织蛋白酶D的酶活性诱导含有载脂蛋白B-100 的脂蛋白（包括 LDL）的水解修饰，这意味着它也可能与动脉粥样硬化有关。^[19][27]

相互作用

• 胃酶抑素^[28]
• 转谷氨酰胺酶2^[29]
• 血红素结合蛋白1（HEBP1）^[30]
• α-2-巨球蛋白（A2M)^[31]
• 神经酰胺^[32]

参考文献

1. 與组织蛋白酶D相關的疾病；在維基數據上查看/編輯參考.
2. GRCh38: Ensembl release 89: ENSG00000117984 - Ensembl, May 2017
3. GRCm38: Ensembl release 89: ENSMUSG00000007891 - Ensembl, May 2017
4. Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
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23. Jha, Sawan Kumar; Rauniyar, Khushbu; Chronowska, Ewa; Mattonet, Kenny; Maina, Eunice Wairimu; Koistinen, Hannu; Stenman, Ulf-Håkan; Alitalo, Kari; Jeltsch, Michael. KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D. eLife. 2019-05-17, 8: –44478. ISSN 2050-084X. PMC 6588350 . PMID 31099754. doi:10.7554/eLife.44478.
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28. Umezawa H, Aoyagi T, Morishima H, Matsuzaki M, Hamada M. Pepstatin, a new pepsin inhibitor produced by Actinomycetes. The Journal of Antibiotics. May 1970, 23 (5): 259–62. PMID 4912600. doi:10.7164/antibiotics.23.259 .
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30. Devosse T, Dutoit R, Migeotte I, De Nadai P, Imbault V, Communi D, Salmon I, Parmentier M. Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3. Journal of Immunology. August 2011, 187 (3): 1475–85. PMID 21709160. doi:10.4049/jimmunol.1003545 .
31. Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, Cherubini A, Metastasio A, Pilotto A, Senin U, Mecocci P. Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease. Journal of the Neurological Sciences. September 2006, 247 (2): 187–91. PMID 16784755. S2CID 34224448. doi:10.1016/j.jns.2006.05.043.
32. Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, Weber T, Saftig P, Peters C, Brunner J, Krönke M, Schütze S. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. The EMBO Journal. October 1999, 18 (19): 5252–63. PMC 1171596 . PMID 10508159. doi:10.1093/emboj/18.19.5252.

更多阅读

• Chao J, Miao RQ, Chen V, Chen LM, Chao L. Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. Biological Chemistry. January 2001, 382 (1): 15–21. PMID 11258665. S2CID 33204682. doi:10.1515/BC.2001.003.
• Leto G, Tumminello FM, Crescimanno M, Flandina C, Gebbia N. Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications. Clinical & Experimental Metastasis. 2004, 21 (2): 91–106. PMID 15168727. S2CID 3476324. doi:10.1023/B:CLIN.0000024740.44602.b7.
• Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prébois C, Rochefort H, Vignon F. Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Letters. June 2006, 237 (2): 167–79 [2022-09-18]. PMID 16046058. doi:10.1016/j.canlet.2005.06.007. （原始内容存档于2022-09-21）.
• Knight CG, Barrett AJ. Interaction of human cathepsin D with the inhibitor pepstatin. The Biochemical Journal. April 1976, 155 (1): 117–25. PMC 1172808 . PMID 938470. doi:10.1042/bj1550117.
• Gulnik S, Baldwin ET, Tarasova N, Erickson J. Human liver cathepsin D. Purification, crystallization and preliminary X-ray diffraction analysis of a lysosomal enzyme. Journal of Molecular Biology. September 1992, 227 (1): 265–70 [2022-09-18]. PMID 1522590. doi:10.1016/0022-2836(92)90696-H. （原始内容存档于2022-09-22）.
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外部链接

• The MEROPS online database for peptidases and their inhibitors: A01.009 （页面存档备份，存于互联网档案馆）
• GeneReviews/NIH/NCBI/UW entry on Neuronal Ceroid-Lipofuscinoses （页面存档备份，存于互联网档案馆）
• PDBe-KB （页面存档备份，存于互联网档案馆） provides an overview of all the structure information available in the PDB for Human Cathepsin D