组织蛋白酶Z
位於20號人類染色體的基因
组织蛋白酶Z，也称为组织蛋白酶X或组织蛋白酶P，是一种在人体中由CTSZ基因编码的蛋白质。[6][7]它是半胱氨酸蛋白酶的半胱氨酸组织蛋白酶家族的成员，该家族有11个成员。[8]作为11种组织蛋白酶之一，组织蛋白酶Z具有与众不同的特征。据报道，组织蛋白酶Z与恶性肿瘤和炎症有关。
结构
基因
CTSZ基因位于20号染色体的20q13.32，由6个外显子组成。已发现该基因的至少两种转录变体，但仅确定了其中一种的全长性质。[7]
蛋白质
组织蛋白酶Z的特点是在假定的氧离子孔的谷氨酰胺和活性位点半胱氨酸之间的高度保守区域中插入了不寻常且独特的3个氨基酸。组织蛋白酶Z的前区与其他组织蛋白酶家族序列没有显着相似性。[9]它仅包含41个氨基酸残基，没有在其他半胱氨酸蛋白酶中发现的ERFNIN或GNFD的保守基序。此外，前区序列不含赖氨酸残基。
功能
该基因编码的蛋白质是一种溶酶体半胱氨酸蛋白酶，是肽酶C1家族的成员。它表现出羧单肽酶和羧二肽酶活性。迄今为止，已鉴定出11种人类半胱氨酸蛋白酶，包括组织蛋白酶B、组织蛋白酶C、组织蛋白酶F、组织蛋白酶H、组织蛋白酶K、组织蛋白酶L1、组织蛋白酶L2或V、组织蛋白酶O、组织蛋白酶S、组织蛋白酶Z和组织蛋白酶W。这些半胱氨酸蛋白酶属于木瓜蛋白酶家族，是溶酶体蛋白酶解系统的主要成分。除了在蛋白质降解和转换中发挥关键作用外，这些蛋白酶似乎在许多正常和病理条件下发挥细胞外作用。人类组织蛋白酶Z包含与其他人类半胱氨酸蛋白酶不同的特征。[10]它是一种具有严格羧肽酶活性的外肽酶，而大多数其他组织蛋白酶是内肽酶。[8]组织蛋白酶Z在酶的前肽内具有暴露的整合素结合Arg-Gly-Asp基序，已显示组织蛋白酶Z在正常体内平衡、免疫过程和癌症期间通过该基序与几种整合素相互作用。[11][12][13][14]它还显示与细胞表面的硫酸肝素蛋白聚糖结合，表明可能在细胞黏附和吞噬作用中发挥作用。[15]
临床意义
该基因在癌细胞系和原发性肿瘤中普遍表达，并且与该家族的其他成员一样，可能参与肿瘤发生。例如，组织蛋白酶Z通过非催化机制促进侵袭和迁移，这表明多种细胞侵袭模式可能与恶性肿瘤有关。[14]组织蛋白酶Z在炎症性胃病中也具有保护作用，但不是蛋白酶解作用。[16]在另一项研究中显示，组织蛋白酶Z可能是导致多巴胺神经元死亡的原因，因此参与了致病级联事件。[17]组织蛋白酶Z中的单核苷酸多态性被发现与结核病易感性有关，表明涉及该蛋白质的途径可以产生结核病的新疗法。[18]
相互作用
组织蛋白酶Z已被证明与以下蛋白质相互作用：CEP55, FBXO6, KIFC1, KRT40, KRTAP5-9, KRTAP5-9, LYPLAL1, MID2, MSN, MTUS2, NOTCH2NL, PLK2, PLSCR1, SGOL2, and SPRED2.[19]
还发现组织蛋白酶Z与以下物质相互作用：
参考文献
- ^ 對Cathepsin Z起作用的藥物；在維基數據上查看/編輯參考.
- ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000101160 - Ensembl, May 2017
- ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000016256 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Santamaría I, Velasco G, Pendás AM, Fueyo A, López-Otín C. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. The Journal of Biological Chemistry. July 1998, 273 (27): 16816–23. PMID 9642240. doi:10.1074/jbc.273.27.16816
.
- ^ 7.0 7.1 Entrez Gene: CTSZ cathepsin Z. [2022-11-01]. （原始内容存档于2010-03-08）.
- ^ 8.0 8.1 Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. January 2012, 1824 (1): 68–88. PMC 7105208 . PMID 22024571. doi:10.1016/j.bbapap.2011.10.002 .
- ^ Nägler DK, Zhang R, Tam W, Sulea T, Purisima EO, Ménard R. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry. September 1999, 38 (39): 12648–54. PMID 10504234. doi:10.1021/bi991371z.
- ^ Nägler DK, Ménard R. Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Letters. August 1998, 434 (1–2): 135–9. PMID 9738465. S2CID 22899822. doi:10.1016/s0014-5793(98)00964-8 .
- ^ Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. The Journal of Biological Chemistry. December 2006, 281 (51): 39588–97. PMID 17065156. doi:10.1074/jbc.M513439200 .
- ^ Kos J, Jevnikar Z, Obermajer N. The role of cathepsin X in cell signaling. Cell Adhesion & Migration. April–June 2009, 3 (2): 164–6. PMC 2679876 . PMID 19262176. doi:10.4161/cam.3.2.7403.
- ^ Obermajer N, Svajger U, Bogyo M, Jeras M, Kos J. Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X. Journal of Leukocyte Biology. November 2008, 84 (5): 1306–15. PMC 3252843 . PMID 18701767. doi:10.1189/jlb.0508285.
- ^ 14.0 14.1 14.2 Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix. Genes & Development. October 2014, 28 (19): 2134–50. PMC 4180975 . PMID 25274726. doi:10.1101/gad.249599.114.
- ^ 15.0 15.1 Teller A, Jechorek D, Hartig R, Adolf D, Reißig K, Roessner A, Franke S. Dysregulation of apoptotic signaling pathways by interaction of RPLP0 and cathepsin X/Z in gastric cancer. Pathology, Research and Practice. January 2015, 211 (1): 62–70. PMID 25433997. doi:10.1016/j.prp.2014.09.005.
- ^ Krueger S, Bernhardt A, Kalinski T, Baldensperger M, Zeh M, Teller A, Adolf D, Reinheckel T, Roessner A, Kuester D. Induction of premalignant host responses by cathepsin x/z-deficiency in Helicobacter pylori-infected mice. PLOS ONE. 2013, 8 (7): e70242. PMC 3728094 . PMID 23936173. doi:10.1371/journal.pone.0070242 .
- ^ Pišlar AH, Zidar N, Kikelj D, Kos J. Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells. Neuropharmacology. July 2014, 82: 121–31. PMID 23958447. S2CID 22499368. doi:10.1016/j.neuropharm.2013.07.040.
- ^ Adams LA, Möller M, Nebel A, Schreiber S, van der Merwe L, van Helden PD, Hoal EG. Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility. European Journal of Human Genetics. June 2011, 19 (6): 676–81. PMC 3110050 . PMID 21368909. doi:10.1038/ejhg.2011.1.
- ^ CTSZ interaction network. BioGRID. [6 August 2016]. （原始内容存档于2022-11-01）.
- ^ Hafner A, Glavan G, Obermajer N, Živin M, Schliebs R, Kos J. Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X. Aging Cell. August 2013, 12 (4): 604–14. PMID 23621429. S2CID 23835547. doi:10.1111/acel.12093 .
阅读
- Nägler DK, Ménard R. Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Letters. August 1998, 434 (1–2): 135–9. PMID 9738465. S2CID 22899822. doi:10.1016/S0014-5793(98)00964-8 .
- Pungercar J, Ivanovski G. Identification and molecular cloning of cathepsin P, a novel human putative cysteine protease of the papain family. Pflügers Archiv. 2000, 439 (3 Suppl): R116–8. PMID 10653162. S2CID 22775842. doi:10.1007/s004240000112.
- Pungercar J, Viyjak A, Ivanovski G, Krizaj I. Tissue expression and immunolocalization of a novel human cathepsin P. Pflügers Archiv. 2000, 439 (3 Suppl): R119–21. PMID 10653163. S2CID 22728027. doi:10.1007/s004240000113.
- Sivaraman J, Nägler DK, Zhang R, Ménard R, Cygler M. Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. Journal of Molecular Biology. January 2000, 295 (4): 939–51. PMID 10656802. doi:10.1006/jmbi.1999.3410.
- Guncar G, Klemencic I, Turk B, Turk V, Karaoglanovic-Carmona A, Juliano L, Turk D. Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease. Structure. March 2000, 8 (3): 305–13 [2022-11-01]. PMID 10745011. doi:10.1016/S0969-2126(00)00108-8. （原始内容存档于2022-03-08）.
- Deussing J, von Olshausen I, Peters C. Murine and human cathepsin Z: cDNA-cloning, characterization of the genes and chromosomal localization. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. April 2000, 1491 (1–3): 93–106. PMID 10760573. doi:10.1016/s0167-4781(00)00021-x.
- Bonthron DT, Hayward BE, Moran V, Strain L. Characterization of TH1 and CTSZ, two non-imprinted genes downstream of GNAS1 in chromosome 20q13. Human Genetics. August 2000, 107 (2): 165–75. PMID 11030415. S2CID 25570066. doi:10.1007/s004390000344.
- Hartley JL, Temple GF, Brasch MA. DNA cloning using in vitro site-specific recombination. Genome Research. November 2000, 10 (11): 1788–95. PMC 310948 . PMID 11076863. doi:10.1101/gr.143000.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S. Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. EMBO Reports. September 2000, 1 (3): 287–92. PMC 1083732 . PMID 11256614. doi:10.1093/embo-reports/kvd058.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A. From ORFeome to biology: a functional genomics pipeline. Genome Research. October 2004, 14 (10B): 2136–44. PMC 528930 . PMID 15489336. doi:10.1101/gr.2576704.
- Puzer L, Barros NM, Oliveira V, Juliano MA, Lu G, Hassanein M, Juliano L, Mason RW, Carmona AK. Defining the substrate specificity of mouse cathepsin P. Archives of Biochemistry and Biophysics. March 2005, 435 (1): 190–6. PMID 15680921. doi:10.1016/j.abb.2004.12.007.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S. The LIFEdb database in 2006. Nucleic Acids Research. January 2006, 34 (Database issue): D415–8. PMC 1347501 . PMID 16381901. doi:10.1093/nar/gkj139.
- Lechner AM, Assfalg-Machleidt I, Zahler S, Stoeckelhuber M, Machleidt W, Jochum M, Nägler DK. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. The Journal of Biological Chemistry. December 2006, 281 (51): 39588–97. PMID 17065156. doi:10.1074/jbc.M513439200 .