Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.
Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C.
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阿尔茨海默病相关的早老蛋白-1 的蛋白水解过程产生蛋白激酶 C 的体内底物。
DOI：
10.1073/pnas.94.10.5349
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发表时间：
1997
影响因子：
11.1
通讯作者：
Haass,C
中科院分区：
文献类型：
--
作者：
Walter,J;Grünberg,J;Capell,A;Pesold,B;Schindzielorz,A;Citron,M;Mendla,K;George-Hyslop,PS;Multhaup,G;Selkoe,DJ;Haass,C
大多数家族性阿尔茨海默病的突变与最近克隆的早老素（PS）基因有关，该基因编码两种高度同源的蛋白质（PS-1和PS-2）。结果表明，全长PS-2蛋白是组成性磷酸化的N-末端结构域内的酪蛋白激酶，而PS-1蛋白不是。全长PS蛋白在其亲水性环结构域内经历内切蛋白水解切割，导致形成1020-kDa C末端片段（CTF）和1030-kDa N末端片段[Thinakaran，G.，等人等（1996）Neuron 17，181-190]。在这里，我们描述了令人惊讶的发现，CTF的PS-1是磷酸化的蛋白激酶C（PKC）。PKC的刺激导致PS-1的120-kDa CTF的磷酸化增加4至5倍，导致SDS凝胶中的迁移率降低。PKC刺激的磷酸化主要发生在丝氨酸残基上，并且可以通过用佛波醇-12，13-二丁酸酯直接刺激PKC或通过用毒蕈碱激动剂卡巴胆碱激活M1乙酰胆碱受体信号传导途径来诱导。然而，全长PS-1和PS-2的磷酸化在PKC刺激后不改变。此外，缺乏外显子10的PS-1的突变形式，其不经历蛋白内切酶切[Thinakaran，G.，等人（1996）Neuron 17，181-190]不被PKC磷酸化，尽管它仍然含有在不同物种之间保守的所有PKC磷酸化位点。这些结果表明PKC磷酸化PS-1 CTF。因此，全长PS-1的内切蛋白水解切割导致产生PKC的非体内底物。PS-1 CTF的选择性磷酸化表明CTF的生理和/或病理性质受PKC活性调节。
The majority of familial Alzheimer disease mutations are linked to the recently cloned presenilin (PS) genes, which encode two highly homologous proteins (PS-1 and PS-2). It was shown that the full-length PS-2 protein is phosphorylated constitutively within its N-terminal domain by casein kinases, whereas the PS-1 protein is not. Full-length PS proteins undergo endoproteolytic cleavage within their hydrophilic loop domain resulting in the formation of ≈20-kDa C-terminal fragments (CTF) and ≈30-kDa N-terminal fragments [Thinakaran, G.,et al.(1996)Neuron17, 181–190]. Here we describe the surprising finding that the CTF of PS-1 is phosphorylated by protein kinase C (PKC). Stimulation of PKC causes a 4- to 5-fold increase of the phosphorylation of the ≈20-kDa CTF of PS-1 resulting in reduced mobility in SDS gels. PKC-stimulated phosphorylation occurs predominantly on serine residues and can be induced either by direct stimulation of PKC with phorbol-12,13-dibutyrate or by activation of the m1 acetylcholine receptor-signaling pathway with the muscarinic agonist carbachol. However, phosphorylation of full-length PS-1 and PS-2 is not altered upon PKC stimulation. In addition, a mutant form of PS-1 lacking exon 10, which does not undergo endoproteolytic cleavage [Thinakaran, G.,et al.(1996)Neuron17, 181–190] is not phosphorylated by PKC, although it still contains all PKC phosphorylation sites conserved between different species. These results show that PKC phosphorylates the PS-1 CTF. Therefore, endoproteolytic cleavage of full-length PS-1 results in the generation of anin vivosubstrate for PKC. The selective phosphorylation of the PS-1 CTF indicates that the physiological and/or pathological properties of the CTF are regulated by PKC activity.
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影响因子：
30.8
作者：
C. Broeckhoven;H. Backhovens;M. Cruts;G. D. Winter;M. Bruyland;P. Cras;Jean-Jacques Martin
通讯作者：
C. Broeckhoven;H. Backhovens;M. Cruts;G. D. Winter;M. Bruyland;P. Cras;Jean-Jacques Martin
阿尔茨海默病（一种异质性疾病）的基因剖析。
DOI：
10.1073/pnas.92.19.8552
发表时间：
1995
影响因子：
11.1
作者：
Schellenberg,GD
通讯作者：
Schellenberg,GD
使用 N 末端特异性单克隆抗体表征人早老素 1：阿尔茨海默病突变影响蛋白水解加工的证据
影响因子：
3.5
作者：
M. Mercken;Hiroshi Takahashi;T. Honda;Kazuki Sato;M. Murayama;Y. Nakazato;K. Noguchi;Kasutomo Imahori;A. Takashima
通讯作者：
A. Takashima
影响因子：
4.8
作者：
DeStrooper, B;Beullens, M;VanLeuven, F
通讯作者：
VanLeuven, F
DOI：
10.1073/pnas.90.19.9195
发表时间：
1993-10-01
影响因子：
11.1
作者：
BUXBAUM, JD;KOO, EH;GREENGARD, P
通讯作者：
GREENGARD, P