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组织蛋白酶D

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维基百科，自由的百科全书
组织蛋白酶D
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名CTSD；, CLN10, CPSD, HEL-S-130P, cathepsin D
外部IDOMIM：116840 MGI：88562 HomoloGene：55616 GeneCards：CTSD
相關疾病
neuronal ceroid lipofuscinosis 10、​神經元蠟樣脂褐質儲積症[1]
基因位置（人类）
11號染色體
染色体11號染色體[2]
11號染色體
组织蛋白酶D的基因位置
组织蛋白酶D的基因位置
基因座11p15.5起始1,752,752 bp[2]
终止1,764,573 bp[2]
RNA表达模式


查阅更多表达数据
直系同源
物種人類小鼠
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 MbChr 7: 141.93 – 141.94 Mb
PubMed​查找[4][5]
維基數據
檢視/編輯人類檢視/編輯小鼠

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尔茨海默病症。[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]

结构

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基因

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CTSD基因位于11号染色体。

蛋白质

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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

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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活化和降解、酶前体的活化、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

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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尔茨海默病风险有强烈影响。[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

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参考文献

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  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. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000117984 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 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. 
  6. ^ Faust PL, Kornfeld S, Chirgwin JM. Cloning and sequence analysis of cDNA for human cathepsin D. Proceedings of the National Academy of Sciences of the United States of America. August 1985, 82 (15): 4910–4. Bibcode:1985PNAS...82.4910F. PMC 390467 可免费查阅. PMID 3927292. doi:10.1073/pnas.82.15.4910 可免费查阅. 
  7. ^ 7.0 7.1 Entrez Gene: CTSD cathepsin D. [2022-09-18]. （原始内容存档于2010-04-12）. 
  8. ^ Barrett AJ. Cathepsin D. Purification of isoenzymes from human and chicken liver. The Biochemical Journal. April 1970, 117 (3): 601–7. PMC 1178965 可免费查阅. PMID 5419752. doi:10.1042/bj1170601. 
  9. ^ Diment S, Martin KJ, Stahl PD. Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins. The Journal of Biological Chemistry. August 1989, 264 (23): 13403–6. PMID 2760027. doi:10.1016/S0021-9258(18)80010-2 可免费查阅. 
  10. ^ 10.0 10.1 Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Köster A, Hess B, Evers M, von Figura K. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. The EMBO Journal. August 1995, 14 (15): 3599–608. PMC 394433 可免费查阅. PMID 7641679. doi:10.1002/j.1460-2075.1995.tb00029.x. 
  11. ^ 11.0 11.1 Ramirez-Montealegre D, Rothberg PG, Pearce DA. Another disorder finds its gene. Brain. June 2006, 129 (Pt 6): 1353–6. PMID 16738059. doi:10.1093/brain/awl132 可免费查阅. 
  12. ^ Metcalf P, Fusek M. Two crystal structures for cathepsin D: the lysosomal targeting signal and active site. The EMBO Journal. April 1993, 12 (4): 1293–302. PMC 413340 可免费查阅. PMID 8467789. doi:10.1002/j.1460-2075.1993.tb05774.x. 
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  15. ^ Authier F, Metioui M, Fabrega S, Kouach M, Briand G. Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D. The Journal of Biological Chemistry. March 2002, 277 (11): 9437–46. PMID 11779865. doi:10.1074/jbc.M110188200 可免费查阅. 
  16. ^ Lee AY, Gulnik SV, Erickson JW. Conformational switching in an aspartic proteinase. Nature Structural Biology. October 1998, 5 (10): 866–71 [2022-09-18]. PMID 9783744. S2CID 5685201. doi:10.1038/2306. （原始内容存档于2022-09-22）. 
  17. ^ Petsko G, Ringe D. Protein Structure and Function. Oxford [England]; Sunderland, MA; New York: Oxford University Press. 2004. ISBN 978-1-4051-1922-1. 
  18. ^ Baechle D, Flad T, Cansier A, Steffen H, Schittek B, Tolson J, et al. Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L. The Journal of Biological Chemistry. March 2006, 281 (9): 5406–15. PMID 16354654. doi:10.1074/jbc.M504670200 可免费查阅. 
  19. ^ 19.0 19.1 Hakala JK, Oksjoki R, Laine P, Du H, Grabowski GA, Kovanen PT, Pentikäinen MO. Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions. Arteriosclerosis, Thrombosis, and Vascular Biology. August 2003, 23 (8): 1430–6. PMID 12750117. doi:10.1161/01.ATV.0000077207.49221.06 可免费查阅. 
  20. ^ Bańkowska A, Gacko M, Chyczewska E, Worowska A. Biological and diagnostic role of cathepsin D. Roczniki Akademii Medycznej W Białymstoku. 1997,. 42 Suppl 1: 79–85. PMID 9337526. 
  21. ^ 21.0 21.1 Benes P, Vetvicka V, Fusek M. Cathepsin D—many functions of one aspartic protease. Critical Reviews in Oncology/Hematology. October 2008, 68 (1): 12–28. PMC 2635020 可免费查阅. PMID 18396408. doi:10.1016/j.critrevonc.2008.02.008. 
  22. ^ Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. Journal of Cell Science. October 2004, 117 (Pt 21): 5155–64. PMID 15456852. doi:10.1242/jcs.01396 可免费查阅. 
  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 可免费查阅. PMID 31099754. doi:10.7554/eLife.44478. 
  24. ^ Traynor JP, Oun HA, McKenzie P, Shilliday IR, McKay IG, Dunlop A, Geddes CC, Mactier RA. Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration. Nephrology, Dialysis, Transplantation. November 2005, 20 (11): 2479–84. PMID 16046508. doi:10.1093/ndt/gfi021 可免费查阅. 
  25. ^ Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L. Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. The American Journal of Pathology. April 2003, 162 (4): 1183–90. PMC 1851240 可免费查阅. PMID 12651610. doi:10.1016/S0002-9440(10)63914-4. 
  26. ^ Menzer G, Müller-Thomsen T, Meins W, Alberici A, Binetti G, Hock C, Nitsch RM, Stoppe G, Reiss J, Finckh U. Non-replication of association between cathepsin D genotype and late onset Alzheimer disease. American Journal of Medical Genetics. March 2001, 105 (2): 179–82. PMID 11304834. doi:10.1002/ajmg.1204. 
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  29. ^ Kim SJ, Kim KH, Ahn ER, Yoo BC, Kim SY. Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival. Amino Acids. January 2013, 44 (1): 73–80. PMID 21960143. S2CID 17149825. doi:10.1007/s00726-011-1089-6. 
  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 可免费查阅. 
  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 可免费查阅. PMID 10508159. doi:10.1093/emboj/18.19.5252. 

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外部链接

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