胱天蛋白酶3

胱天蛋白酶3
已知的結構
PDB	直系同源搜尋: PDBe RCSB
PDBID列表
	1CP3、1GFW、1I3O、1NME、1NMQ、1NMS、1PAU、1QX3、1RE1、1RHJ、1RHK、1RHM、1RHQ、1RHR、1RHU、2C1E、2C2K、2C2M、2C2O、2CDR、2CJX、2CJY、2CNK、2CNL、2CNN、2CNO、2DKO、2H5I、2H5J、2H65、2J30、2J31、2J32、2J33、2XYG、2XYH、2XYP、2XZD、2XZT、2Y0B、3DEH、3DEI、3DEJ、3DEK、3EDQ、3GJQ、3GJR、3GJS、3GJT、3H0E、3ITN、3KJF、3PCX、3PD0、3PD1、4DCJ、4DCO、4DCP、4EHA、4EHD、4EHF、4EHH、4EHK、4EHL、4EHN、4JJE、4JQY、4JQZ、4JR0、4PRY、4PS0、4QTX、4QTY、4QU0、4QU5、4QU8、4QU9、4QUA、4QUB、4QUD、4QUE、4QUG、4QUH、4QUI、4QUJ、4QUL、5IC4
識別號
別名	CASP3；, CPP32, CPP32B, SCA-1, caspase 3
外部ID	OMIM：600636 MGI：107739 HomoloGene：37912 GeneCards：CASP3
為以下藥物的標靶
	emricasan
基因位置（小鼠）
染色體	小鼠8號染色體
終止	47,092,724 bp
RNA表現模式
	查閱更多表現資料
基因本體
分子功能	• 半胱胺酸型肽酶活性; • 肽酶活性; • 血漿蛋白結合; • phospholipase A2 activator activity; • cyclin-dependent protein serine/threonine kinase inhibitor activity; • cysteine-type endopeptidase activity involved in apoptotic process; • cysteine-type endopeptidase activity involved in execution phase of apoptosis; • cysteine-type endopeptidase activity; • 水解酶活性; • cysteine-type endopeptidase activator activity involved in apoptotic process; • aspartic-type endopeptidase activity; • 蛋白酶結合; • death receptor binding; • 大分子複合物結合; • cysteine-type endopeptidase activity involved in apoptotic signaling pathway;
細胞組分	• 細胞質; • 細胞質基質; • 核質; • 死亡誘導信號復合體; • 脂筏模型; • 細胞核; • neuronal cell body;
生物學過程	• cellular response to organic substance; • neuron apoptotic process; • cell fate commitment; • response to estradiol; • intracellular signal transduction; • response to hypoxia; • response to amino acid; • apoptotic DNA fragmentation; • response to organic cyclic compound; • negative regulation of cyclin-dependent protein serine/threonine kinase activity; • response to antibiotic; • platelet formation; • protein processing; • response to nicotine; • response to metal ion; • negative regulation of cell cycle; • 傷口癒合; • response to glucocorticoid; • cellular response to organic cyclic compound; • B cell homeostasis; • negative regulation of apoptotic process; • sensory perception of sound; • response to glucose; • response to organic substance; • hippo signaling; • glial cell apoptotic process; • keratinocyte differentiation; • 蛋白酶解; • cellular response to DNA damage stimulus; • T cell homeostasis; • response to tumor necrosis factor; • negative regulation of activated T cell proliferation; • 心臟發育; • response to lipopolysaccharide; • positive regulation of neuron apoptotic process; • response to wounding; • neuron differentiation; • extrinsic apoptotic signaling pathway in absence of ligand; • 學習和記憶; • positive regulation of apoptotic process; • erythrocyte differentiation; • apoptotic signaling pathway; • negative regulation of B cell proliferation; • response to cobalt ion; • hippocampus development; • response to UV; • response to X-ray; • response to hydrogen peroxide; • regulation of macroautophagy; • neurotrophin TRK receptor signaling pathway; • execution phase of apoptosis; • intrinsic apoptotic signaling pathway in response to osmotic stress; • cellular response to staurosporine; • 細胞凋亡; • cytokine-mediated signaling pathway; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • positive regulation of catalytic activity; • 黃體溶解; • axonal fasciculation; • striated muscle cell differentiation; • leukocyte apoptotic process; • regulation of protein stability; • positive regulation of amyloid-beta formation; • anterior neural tube closure;
	Sources:Amigo / QuickGO
直系同源
	836
	12367
	ENSG00000164305
	ENSMUSG00000031628
	P42574
	P70677
	NM_004346; NM_032991
	NM_009810; NM_001284409
NP_004337; NP_116786; NP_001341706; NP_001341708; NP_001341709;
	NP_001341710; NP_001341711; NP_001341712; NP_001341713
	NP_001271338; NP_033940
	維基資料
檢視/編輯人類	檢視/編輯小鼠

胱天蛋白酶3（英語：Caspase 3）是一種在人類中由CASP3基因編碼的酶。該酶能與胱天蛋白酶8和胱天蛋白酶9產生相互作用。許多可獲得完整基因組資料的哺乳動物都已鑑定出CASP3直系同源物。^[5]鳥類、蜥蜴、滑體動物和真骨類中也存在獨特的直系同源物。

胱天蛋白酶3是胱天蛋白酶（Caspase）家族的成員。^[6]胱天蛋白酶的連續活化在細胞凋亡的執行階段發揮著核心作用。胱天蛋白酶以無活性的酶原形式存在，在保守的天門冬胺酸殘基處經歷蛋白水解加工，產生一大一小兩個亞基，然後二聚化形成活性酶。該蛋白酶可裂解並活化胱天蛋白酶6和7，其本身則由胱天蛋白酶8、9和10加工和活化。該蛋白酶是參與裂解前類澱粉蛋白質的主要胱天蛋白酶，而前類澱粉蛋白質與阿茲海默症中的神經元死亡有關。^[7]該基因的選擇性剪接會產生編碼相同蛋白質的兩個轉錄變體。^[8]

胱天蛋白酶3具有許多目前已知的胱天蛋白酶共有的典型特徵。例如，其活性位點包含半胱胺酸殘基（Cys-163）和組胺酸殘基（His-121），當它位於特定的4個胺基酸序列中時，它能夠穩定蛋白質序列肽鍵裂解到天門冬胺酸的羧基末端側。^[10]^[11]這種特異性使得胱天蛋白酶具有有極高的選擇性，對天門冬胺酸的偏好是麩胺酸的2萬倍。^[12]胱天蛋白酶在細胞中的一個關鍵特徵是它們以未活化的前酶形式存在，稱為胱天蛋白酶原，直到生化變化引起它們的活化為止。每個胱天蛋白酶原都有一個約20kDa的N端大亞基，後面跟著一個約10kDa的小亞基，分別稱為p20和p10。^[13]

受質特異性[編輯]

正常情況下，胱天蛋白酶識別其受質上的四肽序列並水解天門冬胺酸殘基後的肽鍵。胱天蛋白酶3和7通過識別四肽基序Asp-x-x-Asp共享類似的受質特異性。^[14]C端天門冬胺酸是絕對必需的，而其他三個位置的變化是可以容忍的。^[15]胱天蛋白酶受質特異性已廣泛應用於基於胱天蛋白酶的抑制劑和藥物設計。^[16]

結構[編輯]

胱天蛋白酶3（也稱為CPP32、Yama或apopain）^[17]^[18]^[19]是由一個32kDa的酶原形成，該酶原被切割成17kDa和12kDa亞基。當胱天蛋白酶原在特定殘基處裂解時，活性異四聚體就能通過疏水相互作用形成，導致來自p17的四個反平行β摺疊和來自p12的兩個反平行β摺疊結合在一起形成異二聚體，該異二聚體又與另一個異二聚體相互作用形成完整的由α螺旋包圍的12鏈β摺疊結構，這是胱天蛋白酶特有的。^[13]^[20]當異二聚體頭尾相連時，分子兩端各有一個由兩個參與亞基的殘基形成的活性位點，儘管必要的Cys-163和His-121殘基位於p17（較大的）亞基上。^[20]

機制[編輯]

胱天蛋白酶3的催化位點涉及Cys-163的硫醇基團和His-121的咪唑環。His-121穩定關鍵天門冬胺酸殘基的羰基，而Cys-163則攻擊最終裂解肽鍵。Cys-163和Gly-238還可以通過氫鍵穩定受質-酶複合物的四面體過渡態。^[20]在體外，已發現胱天蛋白酶3更喜歡肽序列 DEVDG（Asp-Glu-Val-Asp-Gly），其切割發生在第二個天門冬胺酸殘基的羧基側（D和G之間）。^[12]^[20]^[21]胱天蛋白酶3在較寬的pH範圍內具有活性，該範圍比許多其他執行型胱天蛋白酶稍高（鹼性更強）。這一廣泛的範圍表明胱天蛋白酶3在正常和凋亡細胞條件下都可以完全活躍。^[22]

活化[編輯]

胱天蛋白酶3在凋亡細胞中通過外在（死亡配體）和內在（粒線體）途徑被活化。^[13]^[23]胱天蛋白酶3的酶原特徵是必要的，因為如果不受調節，胱天蛋白酶的活性會不加區別地殺死細胞。^[24]作為執行型胱天蛋白酶，胱天蛋白酶3酶原實際上沒有活性，直到凋亡信號事件發生後被啟動型胱天蛋白酶切割。^[25]此類信號事件之一是將顆粒酶B引入殺傷性T細胞針對凋亡的細胞中，該顆粒酶B可以活化啟動型胱天蛋白酶。^[26]^[27]這種外在活化隨後觸發細胞凋亡途徑的標誌性胱天蛋白酶級聯特徵，其中胱天蛋白酶3發揮主導作用。^[11]在內在活化過程中，來自粒線體的細胞色素c與胱天蛋白酶9、凋亡活化因子1（Apaf-1）和ATP結合作用來處理胱天蛋白酶3酶原。^[21]^[27]^[28]這些分子足以在體外活化胱天蛋白酶3，但體內還需要其他調節蛋白。^[28]山竹（Garcinia mangostana）提取物已被證明可以抑制β澱粉樣蛋白處理的人類神經元細胞中胱天蛋白酶3的活化。^[29]

抑制[編輯]

抑制胱天蛋白酶的一種方法是通過IAP（凋亡抑制劑）蛋白家族，其中包括c-IAP1、c-IAP2、XIAP和ML-IAP。^[20]XIAP結合併抑制啟動型胱天蛋白酶9，後者直接參與執行型胱天蛋白酶3的活化。^[28]然而，在胱天蛋白酶級聯過程中，胱天蛋白酶3通過在特定位點切割胱天蛋白酶9來抑制XIAP的活性，從而阻止XIAP結合來抑制胱天蛋白酶9的活性。^[30]

相互作用[編輯]

胱天蛋白酶3已被證明可以與以下物質相互作用：

生物學功能[編輯]

人們發現胱天蛋白酶3對於正常的大腦發育是必需的，它在細胞凋亡中也發揮著典型作用，負責染色質濃縮和DNA碎裂。^[21]血液中胱天蛋白酶3片段（p17）水平升高是近期心肌梗塞的徵兆。^[52]現在的研究表明，胱天蛋白酶3可能在胚胎和造血幹細胞分化中發揮作用。^[53]

參見[編輯]

參考文獻[編輯]

^ 對Caspase 3起作用的藥物；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCm38: Ensembl release 89: ENSMUSG00000031628 - Ensembl, May 2017
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^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
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^ Ruzzene M, Penzo D, Pinna LA. Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. The Biochemical Journal. May 2002, 364 (Pt 1): 41–7. PMC 1222543 . PMID 11988074. doi:10.1042/bj3640041.
^ Chen YR, Kori R, John B, Tan TH. Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis. Biochemical and Biophysical Research Communications. November 2001, 288 (4): 981–9. PMID 11689006. doi:10.1006/bbrc.2001.5862.
^ Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Research. December 1998, 58 (23): 5315–20. PMID 9850056.
^ Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry. January 2001, 40 (4): 1117–23. PMID 11170436. doi:10.1021/bi001603q.
^ Lee ZH, Lee SE, Kwack K, Yeo W, Lee TH, Bae SS, Suh PG, Kim HH. Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells. Journal of Leukocyte Biology. March 2001, 69 (3): 490–6. PMID 11261798. S2CID 34256107. doi:10.1189/jlb.69.3.490.
^ Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. The Journal of Biological Chemistry. March 2001, 276 (11): 8087–93. PMID 11098060. doi:10.1074/jbc.M009450200 .
^ Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proceedings of the National Academy of Sciences of the United States of America. July 2001, 98 (15): 8662–7. Bibcode:2001PNAS...98.8662S. PMC 37492 . PMID 11447297. doi:10.1073/pnas.161506698 .
^ Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. The Journal of Cell Biology. April 2002, 157 (1): 115–24. PMC 2173256 . PMID 11927604. doi:10.1083/jcb.200108085.
^ Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. Structural basis for the inhibition of caspase-3 by XIAP. Cell. March 2001, 104 (5): 791–800. PMID 11257232. S2CID 17915093. doi:10.1016/S0092-8674(01)00274-4 .
^ Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO Journal. December 1997, 16 (23): 6914–25. PMC 1170295 . PMID 9384571. doi:10.1093/emboj/16.23.6914.
^ Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. July 1997, 388 (6639): 300–4. Bibcode:1997Natur.388..300D. PMID 9230442. S2CID 4395885. doi:10.1038/40901 .
^ Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R. X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes. The Journal of Biological Chemistry. July 2001, 276 (29): 27058–63. PMID 11359776. doi:10.1074/jbc.M102415200 .
^ Ohtsubo T, Kamada S, Mikami T, Murakami H, Tsujimoto Y. Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases. Cell Death and Differentiation. September 1999, 6 (9): 865–72. PMID 10510468. doi:10.1038/sj.cdd.4400566 .
^ Agosto M, Azrin M, Singh K, Jaffe AS, Liang BT. Serum caspase-3 p17 fragment is elevated in patients with ST-segment elevation myocardial infarction: a novel observation. Journal of the American College of Cardiology. January 2011, 57 (2): 220–1. PMID 21211695. doi:10.1016/j.jacc.2010.08.628 .
^ Abdul-Ghani M, Megeney LA. Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation. Cell Stem Cell. June 2008, 2 (6): 515–6. PMID 18522841. doi:10.1016/j.stem.2008.05.013 .

拓展閱讀[編輯]

Cohen GM. Caspases: the executioners of apoptosis. The Biochemical Journal. August 1997, 326 (Pt 1): 1–16. PMC 1218630 . PMID 9337844. doi:10.1042/bj3260001.
Roig J, Traugh JA. Cytostatic p21 G protein-activated protein kinase gamma-PAK. Vitamins & Hormones 62. 2001: 167–98. ISBN 9780127098623. PMID 11345898. doi:10.1016/S0083-6729(01)62004-1.
Zhao LJ, Zhu H. Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design. Current Drug Targets. Immune, Endocrine and Metabolic Disorders. December 2004, 4 (4): 265–75. PMID 15578977. doi:10.2174/1568008043339668.
Le Rouzic E, Benichou S. The Vpr protein from HIV-1: distinct roles along the viral life cycle. Retrovirology. 2006, 2 (1): 11. PMC 554975 . PMID 15725353. doi:10.1186/1742-4690-2-11 .
Sykes MC, Mowbray AL, Jo H. Reversible glutathiolation of caspase-3 by glutaredoxin as a novel redox signaling mechanism in tumor necrosis factor-alpha-induced cell death. Circulation Research. February 2007, 100 (2): 152–4. PMID 17272816. S2CID 12684325. doi:10.1161/01.RES.0000258171.08020.72.

外部連結[編輯]

肽酶及其抑制劑的MEROPS在線資料庫：C14.003 （頁面存檔備份，存於網際網路檔案館）
Apoptosis & Caspase 3 （頁面存檔備份，存於網際網路檔案館） - 蛋白酶解圖譜（英語：The Proteolysis Map）（動畫）

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[pmid11689006-40] Chen YR, Kori R, John B, Tan TH. Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis. Biochemical and Biophysical Research Communications. November 2001, 288 (4): 981–9. PMID 11689006. doi:10.1006/bbrc.2001.5862.

[pmid9850056-41] Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Research. December 1998, 58 (23): 5315–20. PMID 9850056.

[pmid11170436-42] Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, Chung CW, Jung YK, Oh BH. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry. January 2001, 40 (4): 1117–23. PMID 11170436. doi:10.1021/bi001603q.

[pmid11261798-43] Lee ZH, Lee SE, Kwack K, Yeo W, Lee TH, Bae SS, Suh PG, Kim HH. Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells. Journal of Leukocyte Biology. March 2001, 69 (3): 490–6. PMID 11261798. S2CID 34256107. doi:10.1189/jlb.69.3.490.

[pmid11098060-44] Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. The Journal of Biological Chemistry. March 2001, 276 (11): 8087–93. PMID 11098060. doi:10.1074/jbc.M009450200 .

[pmid11447297-45] Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proceedings of the National Academy of Sciences of the United States of America. July 2001, 98 (15): 8662–7. Bibcode:2001PNAS...98.8662S. PMC 37492 . PMID 11447297. doi:10.1073/pnas.161506698 .

[pmid11927604-46] Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. The Journal of Cell Biology. April 2002, 157 (1): 115–24. PMC 2173256 . PMID 11927604. doi:10.1083/jcb.200108085.

[pmid11257232-47] Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. Structural basis for the inhibition of caspase-3 by XIAP. Cell. March 2001, 104 (5): 791–800. PMID 11257232. S2CID 17915093. doi:10.1016/S0092-8674(01)00274-4 .

[pmid9384571-48] Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. The EMBO Journal. December 1997, 16 (23): 6914–25. PMC 1170295 . PMID 9384571. doi:10.1093/emboj/16.23.6914.

[pmid9230442-49] Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. July 1997, 388 (6639): 300–4. Bibcode:1997Natur.388..300D. PMID 9230442. S2CID 4395885. doi:10.1038/40901 .

[pmid11359776-50] Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R. X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes. The Journal of Biological Chemistry. July 2001, 276 (29): 27058–63. PMID 11359776. doi:10.1074/jbc.M102415200 .

[pmid10510468-51] Ohtsubo T, Kamada S, Mikami T, Murakami H, Tsujimoto Y. Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases. Cell Death and Differentiation. September 1999, 6 (9): 865–72. PMID 10510468. doi:10.1038/sj.cdd.4400566 .

[pmid21211695-52] Agosto M, Azrin M, Singh K, Jaffe AS, Liang BT. Serum caspase-3 p17 fragment is elevated in patients with ST-segment elevation myocardial infarction: a novel observation. Journal of the American College of Cardiology. January 2011, 57 (2): 220–1. PMID 21211695. doi:10.1016/j.jacc.2010.08.628 .

[pmid18522841-53] Abdul-Ghani M, Megeney LA. Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation. Cell Stem Cell. June 2008, 2 (6): 515–6. PMID 18522841. doi:10.1016/j.stem.2008.05.013 .

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