OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.
OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation.
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DOI：
10.1093/hmg/ddq088
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Chan DC
中科院分区：
文献类型：
--
作者：
Ban T;Heymann JA;Song Z;Hinshaw JE;Chan DC
动力相关的 GTPase OPA1 在常染色体显性视神经萎缩 (DOA)（Kjer 型）中发生突变，这是一种视网膜神经节细胞的遗传性神经病。 OPA1 对于线粒体内膜的融合至关重要，但其作用机制仍知之甚少。在这里，我们表明 OPA1 的 GTP 水解基础率较低，通过与含有负磷脂（如心磷脂）的脂质体结合，该水解率会显着增强。脂质结合触发 OPA1 组装成更高阶的寡聚物。此外，我们发现OPA1可以促进脂质小管从含心磷脂的脂质体表面突出。在这种脂质突出物中，在脂质小管表面的外部观察到 OPA1 组装体，这是一种类似于经典动力蛋白的蛋白质膜拓扑结构。 GTPγS 抑制 OPA1 的膜管活性。与 DOA 相关的 OPA1 疾病等位基因在多种活动中表现出选择性缺陷，包括心磷脂关联、GTP 水解和膜管化。这些发现表明 OPA1 与膜的相互作用可以刺激高阶组装，增强 GTP 水解并导致膜变形为小管。
The dynamin-related GTPase OPA1 is mutated in autosomal dominant optic atrophy (DOA) (Kjer type), an inherited neuropathy of the retinal ganglion cells. OPA1 is essential for the fusion of the inner mitochondrial membranes, but its mechanism of action remains poorly understood. Here we show that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids such as cardiolipin. Lipid association triggers assembly of OPA1 into higher order oligomers. In addition, we find that OPA1 can promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies are observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 is suppressed by GTPγS. OPA1 disease alleles associated with DOA display selective defects in several activities, including cardiolipin association, GTP hydrolysis and membrane tubulation. These findings indicate that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis and lead to membrane deformation into tubules.
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影响因子：
4.8
作者：
Olichon, A;Baricault, L;Lenaers, G
通讯作者：
Lenaers, G
DOI：
10.1126/science.1171004
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Pucadyil TJ;Schmid SL
通讯作者：
Schmid SL
影响因子：
7.8
作者：
Song, Zhiyin;Chen, Hsiuchen;Fiket, Maja;Alexander, Christiane;Chan, David C.
通讯作者：
Chan, David C.
影响因子：
14.5
作者：
Hudson, Gavin;Amati-Bonneau, Patrizia;Taylor, Robert W.
通讯作者：
Taylor, Robert W.
影响因子：
3.3
作者：
Song, Zhiyin;Ghochani, Mariam;Chan, David C.
通讯作者：
Chan, David C.