A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing.
A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing.
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DOI：
10.1111/j.1471-4159.2012.07680.x
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发表时间：
2012-06
影响因子：
4.7
通讯作者：
Wolfe MS
中科院分区：
文献类型：
--
作者：
Fisette JF;Montagna DR;Mihailescu MR;Wolfe MS
β-位点APP切割酶1 （BACE1）是一种跨膜天冬氨酸蛋白酶，它催化淀粉样β-蛋白前体（APP）水解成淀粉样β-蛋白（a β）的第一步裂解，这一过程与阿尔茨海默病的发病机制有关。BACE1 pre-mRNA经历复杂的选择性剪接，其调控尚不清楚。我们在BACE1的外显子3中发现了一个富含g的序列，参与控制剪接位点的选择。富含g序列的突变减少了外显子3正常5 '剪接位点的使用，从而导致全长和蛋白水解活性的BACE1，并增加了对替代剪接位点的使用，从而导致更短，基本上无活性的同工型。核酸酶保护实验、核磁共振和圆二色光谱显示该序列折叠成g -四重体结构。有几种蛋白质被鉴定为能够与富含g的序列结合，其中一种，异质核核糖核蛋白H (hnRNP H)，被发现以依赖于富含g的序列的方式调节BACE1外显子3的选择性剪接。hnRNP H的敲低导致BACE1全长mRNA亚型的减少以及APP产生a β的减少，这为AD的治疗方法提供了新的可能性。
β-site APP cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the amyloid β-protein precursor (APP) to the amyloid β-protein (Aβ), a process involved in the pathogenesis of Alzheimer disease. BACE1 pre-mRNA undergoes complex alternative splicing, the regulation of which is not well understood. We identified a G-rich sequence within exon 3 of BACE1 involved in controlling splice site selection. Mutation of the G-rich sequence decreased use of the normal 5′ splice site of exon 3, which leads to full-length and proteolytically active BACE1, and increased use of an alternative splice site, which leads to a shorter, essentially inactive isoform. Nuclease protection assays, nuclear magnetic resonance, and circular dichroism spectroscopy revealed that this sequence folds into a G-quadruplex structure. Several proteins were identified as capable of binding to the G-rich sequence, and one of these, heterogeneous nuclear ribonucleoprotein H (hnRNP H), was found to regulate BACE1 exon 3 alternative splicing and in a manner dependent on the G-rich sequence. Knockdown of hnRNP H led to a decrease in the full-length BACE1 mRNA isoform as well as a decrease in Aβ production from APP, suggesting new possibilities for therapeutic approaches to AD.
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影响因子：
4.8
作者：
Garneau, D;Revil, T;Chabot, B
通讯作者：
Chabot, B
影响因子：
5.3
作者：
Laird, FM;Cai, HB;Wong, PC
通讯作者：
Wong, PC
影响因子：
14.9
作者：
SHAPIRO, MB;SENAPATHY, P
通讯作者：
SENAPATHY, P
DOI：
10.1124/jpet.108.138974
发表时间：
2008-08-01
影响因子：
3.5
作者：
Meredith, Jere E., Jr.;Thompson, Lorin A.;Albright, Charles F.
通讯作者：
Albright, Charles F.
影响因子：
4.8
作者：
Villemaire, J;Dion, I;Chabot, B
通讯作者：
Chabot, B