The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria
The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria
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DOI：
10.1097/00008571-200303000-00004
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发表时间：
2003-03-01
期刊：
影响因子：
--
通讯作者：
Degoul, F
中科院分区：
文献类型：
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作者：
Sutton, A;Khoury, H;Degoul, F
人锰超氧化物歧化酶（MnSOD）的线粒体靶向序列（MTS）中编码丙氨酸（Ala）或缬氨酸（瓦尔）的遗传二型性，并且已报道调节某些癌症、神经退行性疾病和严重酒精性肝病的风险。虽然这种二态性对MnSOD活性的功能后果尚未评估，但计算机模型预测Ala-MnSOD/MTS的部分α-螺旋结构，但Val变体的β-折叠结构，这可能会阻碍线粒体输入。为了研究这一假设，我们研究了在体外进口的嵌合蛋白组成的MnSOD/MTS融合到小鼠二氢叶酸还原酶（DHFR）蛋白，和进口的两个人MnSOD前体变体到大鼠肝线粒体。与Ala蛋白相比，Val-MnSOD/MTS-DHFR前体和Val-MnSOD前体均部分滞留在线粒体内膜内。Ala-MnSOD前体比Val-MnSOD前体多产生30-40%的活性、基质、加工的MnSOD同源四聚体。这些结果表明，Ala-MnSOD/MTS允许有效的MnSOD输入到线粒体基质中，而Val-变体导致内膜内的前体的部分停滞和线粒体基质中活性MnSOD四聚体的形成减少。
A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence (MTS) of human manganese superoxide dismutase (MnSOD) and has been reported to modulate the risk of some cancers, neurodegenerative diseases and severe alcoholic liver disease. Although functional consequences of this dimorphism on MnSOD activity have not been assessed, computer models predict a partial cc-helix structure for the Ala-MnSOD/MTS, but a beta-sheet structure for the Val-variant, which could hamper mitochondrial import. To investigate this hypothesis, we studied the in-vitro import of chimaeric proteins composed of either one of the MnSOD/MTS fused to the mouse dihydrofolate reductase (DHFR) protein, and the import of the two human MnSOD precursor variants into rat liver mitochondria. Compared to Ala-proteins, the Val-MnSOD/MTS-DHFR precursor and Val-MnSOD precursor were both partly arrested within the inner mitochondrial membrane. The Ala-MnSOD precursor generated 30-40% more of the active, matricial, processed MnSOD homotetramer than the Val-MnSOD precursor. These results show that the Ala-MnSOD/MTS allows efficient MnSOD import into the mitochondrial matrix, while the Val-variant causes partial arrest of the precursor within the inner membrane and decreased formation of the active MnSOD tetramer in the mitochondrial matrix.