Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Struct Mol Biol. 2020 Feb;27(2):202-209. doi: 10.1038/s41594-020-0373-0. Epub 2020 Feb 10.
The mitochondrial membrane-bound AAA protein Bcs1 translocate substrates across the mitochondrial inner membrane without previous unfolding. One substrate of Bcs1 is the iron-sulfur protein (ISP), a subunit of the respiratory Complex III. How Bcs1 translocates ISP across the membrane is unknown. Here we report structures of mouse Bcs1 in two different conformations, representing three nucleotide states. The apo and ADP-bound structures reveal a homo-heptamer and show a large putative substrate-binding cavity accessible to the matrix space. ATP binding drives a contraction of the cavity by concerted motion of the ATPase domains, which could push substrate across the membrane. Our findings shed light on the potential mechanism of translocating folded proteins across a membrane, offer insights into the assembly process of Complex III and allow mapping of human disease-associated mutations onto the Bcs1 structure.
线粒体外膜结合的 AAA 蛋白 Bcs1 在没有预先展开的情况下将底物跨线粒体内膜转运。Bcs1 的一种底物是铁硫蛋白 (ISP)，它是呼吸复合物 III 的一个亚基。Bcs1 如何将 ISP 跨膜转运尚不清楚。在这里，我们报告了两种不同构象的小鼠 Bcs1 的结构，分别代表了三个核苷酸状态。apo 和 ADP 结合的结构揭示了一个同型七聚体，并显示了一个可通往基质空间的大的潜在底物结合腔。ATP 结合通过 ATP 酶结构域的协同运动驱动腔的收缩，这可能会推动底物跨膜转运。我们的发现揭示了跨膜转运折叠蛋白的潜在机制，深入了解了复合物 III 的组装过程，并允许将与人相关的疾病突变映射到 Bcs1 结构上。
