A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein
A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein
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DOI：
10.1074/jbc.m008861200
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发表时间：
2001-04-13
影响因子：
4.8
通讯作者：
Paganetti, P
中科院分区：
文献类型：
--
作者：
Bodendorf, U;Fischer, F;Paganetti, P
β-分泌酶 (BACE) 启动淀粉样前体蛋白的淀粉样蛋白形成过程，导致产生 β-淀粉样蛋白，这是阿尔茨海默病老年斑的主要成分。 BACE 是一种由 501 个氨基酸组成的 I 型跨膜天冬氨酰蛋白酶。在这里，我们描述了一种缺乏 132 个碱基对的新型 BACE mRNA，它在胰腺中表达，但在大脑中不表达。序列比对表明，删除的片段与外显子 3 的末端三分之二相匹配。新的 BACE 变体缺少位于两个催化天冬氨酰残基之间的 44 个氨基酸区域。因此，在人胰腺中检测到 50 kDa 形式的 BACE (BACE457)。当在细胞中表达时，BACE457 与内质网 BiP 标记共定位。此外，BACE457 仍处于酶原和糖苷内切酶 H 敏感状态，表明其沿着分泌途径的运输在内质网水平上被阻断。值得注意的是，这种新型 BACE 不参与淀粉样前体蛋白的加工。我们的研究结果表明，BACE mRNA 的组织特异性剪接可以解释以下观察结果：在人类胰腺中，BACE 基因的稳健转录并未转化为恢复的酶活性。
beta -Secretase (BACE) initiates the amyloidogenic processing of the amyloid precursor protein leading to the generation of the beta -amyloid, the main component of Alzheimer's disease senile plaques. BACE is a type I transmembrane aspartyl protease of 501 amino acids. Here we describe a novel BACE mRNA lacking 132 base pairs that is expressed in the pancreas but not in the brain. Sequence alignment indicates that the deleted fragment matches the terminal two-thirds of exon 3. The new BACE variant is short of a 44-amino acid region located between the two catalytic aspartyl residues. Accordingly, a 50-kDa form of BACE (BACE457) is detected in the human pancreas. When expressed in cells, BACE457 colocalizes with the marker for the endoplasmic reticulum BiP. Moreover, BACE457 remains in a proenzymatic and endoglycosidase H-sensitive state, suggesting that its transport along the secretory pathway is blocked at the level of the endoplasmic reticulum. Notably, this novel form of BACE does not contribute to the processing of the amyloid precursor protein. Our findings suggest that tissue-specific splicing of the BACE mRNA may explain the observation that in the human pancreas robust transcription of the BACE gene does not translate into recovered enzymatic activity.