胱天蛋白酶8

胱天蛋白酶8
已知的結構
PDB直系同源搜索: PDBe RCSB
PDBID列表

1F9E、​1I4E、​1QDU、​1QTN、​2C2Z、​2FUN、​2K7Z、​2Y1L、​3H11、​3KJN、​3KJQ、​4JJ7、​4PRZ、​4PS1、​4ZBW

識別號
别名CASP8;, ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
外部IDOMIM:601763 MGI:1261423 HomoloGene:7657 GeneCards:CASP8
相關疾病
caspase-8 deficiency[1]
為以下藥物的標靶
emricasan[2]
基因位置(人类
2號染色體
染色体2號染色體[3]
2號染色體
胱天蛋白酶8的基因位置
胱天蛋白酶8的基因位置
基因座2q33.1起始201,233,443 bp[3]
终止201,287,711 bp[3]
基因位置(小鼠
小鼠1号染色体
染色体小鼠1号染色体[4]
小鼠1号染色体
胱天蛋白酶8的基因位置
胱天蛋白酶8的基因位置
基因座1 C1.3|1 29.19 cM起始58,834,533 bp[4]
终止58,886,662 bp[4]
RNA表达模式


查阅更多表达数据
基因本體
分子功能 death effector domain binding
半胱氨酸型肽酶活性
cysteine-type endopeptidase activity involved in apoptotic signaling pathway
scaffold protein binding
血浆蛋白结合
相同蛋白质结合
cysteine-type endopeptidase activity involved in apoptotic process
cysteine-type endopeptidase activity
水解酶活性
泛素蛋白连接酶结合
肽酶活性
cysteine-type endopeptidase activity involved in execution phase of apoptosis
death receptor binding
tumor necrosis factor receptor binding
大分子复合物结合
細胞組分 cell body
细胞质基质
CD95 death-inducing signaling complex
ripoptosome
核质
mitochondrial outer membrane
死亡誘導信號復合體
脂筏模型
neuron projection
细胞骨架
細胞質
線粒體
细胞核
大分子复合体
生物學過程 regulation of apoptotic process
response to estradiol
activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
response to antibiotic
肿瘤坏死因子介导的信号通路的调控
positive regulation of macrophage differentiation
cellular response to organic cyclic compound
natural killer cell activation
negative regulation of I-kappaB kinase/NF-kappaB signaling
TRAIL-activated apoptotic signaling pathway
蛋白酶解
macrophage differentiation
TRIF-dependent toll-like receptor signaling pathway
response to tumor necrosis factor
B cell activation
cell surface receptor signaling pathway
response to lipopolysaccharide
cellular response to mechanical stimulus
activation of cysteine-type endopeptidase activity
positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
death-inducing signaling complex assembly
positive regulation of proteolysis
positive regulation of I-kappaB kinase/NF-kappaB signaling
apoptotic signaling pathway
response to cold
regulation of extrinsic apoptotic signaling pathway via death domain receptors
viral process
response to ethanol
response to cobalt ion
activation of cysteine-type endopeptidase activity involved in apoptotic process
proteolysis involved in cellular protein catabolic process
syncytiotrophoblast cell differentiation involved in labyrinthine layer development
含有信号通路的核苷酸结合寡聚结构域
T细胞活化
suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process
细胞凋亡
extrinsic apoptotic signaling pathway
死亡域受体对外源性凋亡信号通路的负调控
regulation of necroptotic process
execution phase of apoptosis
toll-like receptor 3 signaling pathway
positive regulation of neuron death
extrinsic apoptotic signaling pathway via death domain receptors
positive regulation of interleukin-1 beta production
Sources:Amigo / QuickGO
直系同源
物種人類小鼠
Entrez

841

12370

Ensembl

ENSG00000064012

ENSMUSG00000026029

UniProt

Q14790

O89110

mRNA​序列
​NM_001080124
​NM_001080125
​NM_001228
​NM_033355
​NM_033356

​NM_033357
​NM_033358
​NM_001372051

NM_001080126
​NM_001277926
​NM_009812

蛋白序列
NP_001073593
​NP_001073594
​NP_001219
​NP_203519
​NP_203520

​NP_203522
​NP_001358980

NP_001073595
​NP_001264855
​NP_033942

基因位置​(UCSC)Chr 2: 201.23 – 201.29 MbChr 1: 58.83 – 58.89 Mb
PubMed​查找[5][6]
維基數據
檢視/編輯人類檢視/編輯小鼠

胱天蛋白酶8英语:Caspase 8)是一种胱天蛋白酶,由CASP8基因编码。该酶很可能作用于胱天蛋白酶3。许多可获得完整基因组数据的哺乳动物都已鉴定出CASP8直系同源物[7]这些独特的直系同源物也存在于鸟类中。

作用

胱天蛋白酶8是胱天蛋白酶家族的成员。半胱天冬酶的连续激活在细胞凋亡的执行阶段发挥着核心作用。半胱天冬酶作为无活性酶原存在,由前结构域、大蛋白酶亚基和小蛋白酶亚基组成。半胱天冬酶的激活需要在保守的天冬氨酸残基处经历蛋白水解加工,以产生一大一小两个亚基组成的异二聚体酶。该蛋白参与Fas和各种细胞凋亡刺激诱导的程序性细胞死亡。该蛋白的N端FADD样死亡效应结构域表明它可能与FADD相互作用。这种蛋白质在亨廷顿舞蹈症患者受影响的大脑区域的不溶性部分中检测到,而在正常对照的大脑区域中未检测到,这表明它在神经退行性疾病中的作用。已经描述了许多编码不同亚型的选择性剪接转录物变体,尽管并非所有变体都已确定其全长序列。[8]

临床意义

一种非常罕见的免疫系统遗传性疾病也可能是由该基因的突变引起的。这种疾病称为CEDS,意思是“胱天蛋白酶8缺乏状态”。CEDS具有与另一种细胞凋亡遗传病ALPS 相似的特征,但前者有免疫缺陷表型。因此,除了复发性鼻窦及肺部感染、复发性皮肤粘膜疱疹病、持续性疣和传染性软疣感染以及咖瑪免疫球蛋白過低之外,临床表现还包括脾肿大和淋巴结肿大。主质器官有时存在淋巴细胞浸润性疾病,但自身免疫性极小,而且在CEDS患者中尚未观察到淋巴瘤。CEDS以常染色体隐性方式遗传。[9]

CEDS患者的临床表型呈现出一个悖论,因为胱天蛋白酶8被认为主要是一种促凋亡蛋白酶,主要参与肿瘤坏死因子受体家族死亡受体(例如Fas)的信号转导。淋巴细胞激活和保护性免疫的缺陷表明胱天蛋白酶8在淋巴细胞中具有额外的信号传导作用。进一步的研究表明,胱天蛋白酶8在TB自然杀伤细胞中,通过抗原受体、Fc受体Toll样受体4刺激后,对转录因子“核因子κB”(NF-κB)的诱导至关重要 。[9]

生化方面,发现胱天蛋白酶8进入NF-κB激酶抑制剂(IKK)与上游Bcl10-MALT1(粘膜相关淋巴组织)适配器复合物的复合体中,这对于诱导NF-κB的核转位至关重要 。此外,胱天蛋白酶8的生化形式在这两种途径中是不同的。对于死亡途径,胱天蛋白酶8酶原被切割成亚基,这些亚基组装形成成熟的、高活性的胱天蛋白酶异四聚体;而对于激活途径,酶原似乎保持完整,可能是为了限制其蛋白水解功能,但增强其作为适配器蛋白的功能。[9]

相互作用

胱天蛋白酶8已被证明可以与以下物质相互作用

附加图片

TNF-R1信号通路。灰色虚线表示多个步骤
细胞凋亡涉及的信号转导途径概述

参见

参考文献

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拓展阅读

  • Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC. Dynamic Regulation of Neutrophil Survival through Tyrosine Phosphorylation or Dephosphorylation of Caspase-8. Journal of Biological Chemistry. 2008, 283 (9): 5402–5413. PMID 18086677. doi:10.1074/jbc.M706462200可免费查阅. 
  • Cohen GM. Caspases: the executioners of apoptosis. Biochem. J. 1997, 326 (Pt 1): 1–16. PMC 1218630可免费查阅. PMID 9337844. doi:10.1042/bj3260001. 
  • Siegel RM, Chan FK, Chun HJ, Lenardo MJ. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat. Immunol. 2001, 1 (6): 469–74. PMID 11101867. S2CID 345769. doi:10.1038/82712. 
  • Ye S, Goldsmith EJ. Serpins and other covalent protease inhibitors. Curr. Opin. Struct. Biol. 2002, 11 (6): 740–5. PMID 11751056. doi:10.1016/S0959-440X(01)00275-5. 
  • Gupta S. Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules. Exp. Gerontol. 2002, 37 (2–3): 293–9. PMID 11772515. S2CID 30243363. doi:10.1016/S0531-5565(01)00195-4. 
  • Pomerantz RJ. Effects of HIV-1 Vpr on neuroinvasion and neuropathogenesis. DNA Cell Biol. 2004, 23 (4): 227–38. PMID 15142380. doi:10.1089/104454904773819815. 
  • Zhao LJ, Zhu H. Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005, 4 (4): 265–75. PMID 15578977. doi:10.2174/1568008043339668. 

外部链接

  • 肽酶及其抑制剂的MEROPS在线数据库:C14.009[失效連結]
  • Apoptosis & Caspase 8 (页面存档备份,存于互联网档案馆) - 蛋白酶解图谱英语The Proteolysis Map(动画)
  • 醫學主題詞表(MeSH):Caspase-8
  • Caspase-8 (页面存档备份,存于互联网档案馆
  • PDBUniProt可用的所有結構信息之概述:Q14790 (Caspase-8) 在PDBe-KB英语PDBe-KB
Fas通路
配体
  • Fas配体
受体
  • Fas受体
细胞内
  • 死亡诱导信号复合体
  • DAXX
  • ASK1
  • FADD
  • 半胱天冬酶8
  • BID
促凋亡:
BAX
BAK1/Bcl-2同源性拮抗扼杀剂
Bcl-2相关死亡助剂
抗凋亡:
Bcl-2
Bcl-xL
TNF通路
配体
受体
  • 肿瘤坏死因子受体
细胞内
  • TRADD
  • TRAF2
  • ASK-1
  • MEKK1
  • IKK
  • IκBα
  • MKK7
  • JNK
  • NF-κB
其它
细胞内
凋亡抑制因子
XIAP
NAIP
生存素
c-IAP-1
c-IAP-2
 
信号转导索引
描述
  • 胞外
    • 神經肽
    • 生长因子
    • 细胞因子
    • 激素
  • 細胞表面受體英语Template:Cell surface receptors
    • 配体门控离子通道
    • 酶联受體
    • G蛋白偶聯受體
    • 免疫球蛋白超家族英语Template:Immunoglobulin superfamily immune receptors
    • 整合素
    • 神經肽受體
    • 生長因子受體
    • 细胞因子受體
  • 胞內
    • 受體蛋白英语Template:Signal transducing adaptor proteins
    • GTP-binding英语Template:GTP-binding protein regulators
    • MAP激酶
  • 鈣信號
  • 脂質系號
  • 路徑
    • hedgehog
    • Wnt
    • TGF-β
    • MAPK ERK英语Template:MAPK ERK signaling pathway
    • notch英语Template:Notch signaling pathway
    • JAK-STAT
    • 細胞凋亡
    • hippo英语Template:Hippo signaling pathway
    • TLR
胱天蛋白酶
来自果实
钙蛋白酶
  • CAPN1
  • CAPN2
  • CAPN3
  • CAPN5
  • CAPN6
  • CAPN7
  • CAPN8
  • CAPN9
  • CAPN10
  • CAPN11
  • CAPN12
  • CAPN13
  • CAPN14
  • CAPNS1
  • CAPNS2
组织蛋白酶
其它
EC 1.1/2/3/4/5/6/7/8/9/10/11/12/13/14/15/16/17/18/19/20/21/22 · 2.1/2/3/4/5/6/7(2.7.10/11-12)/8/9 · 3.1/2/3/4(3.4.21/22/23/24)/5/6/7/8/9/10/11/12/13 · 4.1/2/3/4/5/6 · 5.1/2/3/4/5/99 · 6.1-3英语Template:Ligases CO CS and CN/4/5-6
活性
调节
分类
动力学
类型
  • EC1 氧化還原酶列表英语List of EC numbers (EC 1)
  • EC2 轉移酶列表英语List of EC numbers (EC 2)
  • EC3 水解酶列表英语List of EC numbers (EC 3)
  • EC4 裂合酶列表英语List of EC numbers (EC 4)
  • EC5 異構酶列表英语List of EC numbers (EC 5)
  • EC6 連接酶列表英语List of EC numbers (EC 6)
  • EC7 移位酶英语Translocase列表英语List of EC numbers (EC 7)
  • 生物学主题