712 North Inc., QB3 Incubator at UC Berkeley, 130 Stanley Hall, #3220, Berkeley CA-94720, USA.
Biochim Biophys Acta Proteins Proteom. 2021 Feb;1869(2):140558. doi: 10.1016/j.bbapap.2020.140558. Epub 2020 Oct 29.
OMA1 is a mitochondrial protease. Among its substrates are DELE1, a signaling peptide, which can elicit the integrated stress response, as well as the membrane-shaping dynamin-related GTPase OPA1, which can drive mitochondrial outer membrane permeabilization. OMA1 is dormant under physiological conditions but rapidly activated upon mitochondrial stress, such as loss of membrane potential or excessive reactive oxygen species. Accordingly, OMA1 was found to be activated in a number of disease conditions, including cancer and neurodegeneration. OMA1 has a predicted transmembrane domain and is believed to be tethered to the mitochondrial inner membrane. Yet, its structure has not been resolved and its context-dependent regulation remains obscure. Here, I review the literature with focus on OMA1's biochemistry. I provide a good homology model of OMA1's active site with a root-mean-square deviation of 0.9 Å and a DALI Z-score of 19.8. And I build a case for OMA1 actually being an integral membrane protease based on OMA1's role in the generation of small signaling peptides, its functional overlap with PARL, and OMA1's homology with ZMPSTE24. The refined understanding of this important enzyme can help with the design of tool compounds and development of chemical probes in the future.
OMA1 是一种线粒体蛋白酶。其底物包括信号肽 DELE1，它可以引发整合应激反应，以及膜成形的与 dynamin 相关的 GTPase OPA1，它可以驱动线粒体外膜通透性。在生理条件下，OMA1 处于休眠状态，但在诸如膜电位丧失或过多的活性氧等线粒体应激下，它会迅速被激活。因此，在许多疾病状态下，包括癌症和神经退行性疾病，都发现 OMA1 被激活。OMA1 具有预测的跨膜结构域，被认为与线粒体内膜相连。然而，它的结构尚未解析，其上下文相关的调节仍然不清楚。在这里，我重点回顾了 OMA1 的生物化学文献。我提供了一个 OMA1 活性位点的良好同源模型，均方根偏差为 0.9Å，DALI Z 分数为 19.8。并且，我提出了一个观点，即 OMA1 实际上是一种整合膜蛋白酶，这基于 OMA1 在生成小信号肽中的作用、其与 PARL 的功能重叠以及 OMA1 与 ZMPSTE24 的同源性。对这种重要酶的更深入理解有助于未来设计工具化合物和开发化学探针。
