Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Hum Mol Genet. 2010 Jun 1;19(11):2113-22. doi: 10.1093/hmg/ddq088. Epub 2010 Feb 25.
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 GTPgammaS. 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.
动力相关 GTP 酶 OPA1 突变与常染色体显性视神经萎缩（DOA）（Kjer 型）有关，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是必不可少的，但它的作用机制仍知之甚少。在这里，我们表明 OPA1 具有低基础 GTP 水解率，通过与含有心磷脂等负电荷磷脂的脂质体结合可显著增强。脂质体结合触发 OPA1 组装成更高阶的寡聚物。此外，我们发现 OPA1 可以促进含有心磷脂的脂质体表面脂质小管的突出。在这种脂质突起中，OPA1 组装体位于脂质小管表面的外部，这种蛋白-膜拓扑结构类似于经典的动力蛋白。OPA1 的膜小管形成活性被 GTPγS 抑制。与 DOA 相关的 OPA1 疾病等位基因在几种活性中表现出选择性缺陷，包括心磷脂结合、GTP 水解和膜小管形成。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。
