Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor
Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor
复制标题
DOI：
10.1074/jbc.273.43.27765
复制
发表时间：
1998-10-23
影响因子：
4.8
通讯作者：
Black, RA
中科院分区：
文献类型：
--
作者：
Buxbaum, JD;Liu, KN;Black, RA
在阿尔茨海默病患者大脑中积聚的淀粉样蛋白Aβ是由淀粉样蛋白前体（APP）经蛋白水解作用产生的。APP可在三个位点进行内切蛋白水解加工，一个在Aβ结构域的氨基末端（β裂解），一个在Aβ结构域内（α裂解），还有一个在Aβ结构域的羧基末端（γ裂解）。负责这些活性的酶尚未明确确定。通过基因破坏（敲除）技术，我们现在证明肿瘤坏死因子α转换酶（TACE），一种ADAM家族（解聚素和金属蛋白酶家族）的蛋白酶成员，在APP的受调控的α裂解中起核心作用。我们的数据表明，TACE可能是负责培养细胞中大多数受调控的α裂解的α分泌酶。此外，我们还表明抑制这种酶会影响培养细胞中APP的分泌以及Aβ的形成。
The amyloid protein, A beta, which accumulates in the brains of Alzheimer patients, is derived by proteolysis of the amyloid protein precursor (APP). APP can undergo endoproteolytic processing at three sites, one at the amino terminus of the A beta domain (beta-cleavage), one within the A beta domain (alpha-cleavage), and one at the carboxyl terminus of the A beta domain (gamma-cleavage). The enzymes responsible for these activities have not been unambiguously identified. By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells. Furthermore, we show that inhibiting this enzyme affects both APP secretion and A beta formation in cultured cells.