Department of Experimental Medical Science, Lund University, Sölvegatan 19, SE-221 84, Lund, Sweden.
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH, 43210, USA.
Nat Commun. 2022 Jul 27;13(1):4339. doi: 10.1038/s41467-022-32006-8.
In eukaryotes, iron-sulfur clusters are essential cofactors for numerous physiological processes, but these clusters are primarily biosynthesized in mitochondria. Previous studies suggest mitochondrial ABCB7-type exporters are involved in maturation of cytosolic iron-sulfur proteins. However, the molecular mechanism for how the ABCB7-type exporters participate in this process remains elusive. Here, we report a series of cryo-electron microscopy structures of a eukaryotic homolog of human ABCB7, CtAtm1, determined at average resolutions ranging from 2.8 to 3.2 Å, complemented by functional characterization and molecular docking in silico. We propose that CtAtm1 accepts delivery from glutathione-complexed iron-sulfur clusters. A partially occluded state links cargo-binding to residues at the mitochondrial matrix interface that line a positively charged cavity, while the binding region becomes internalized and is partially divided in an early occluded state. Collectively, our findings substantially increase the understanding of the transport mechanism of eukaryotic ABCB7-type proteins.
在真核生物中，铁硫簇是许多生理过程的必需辅因子，但这些簇主要在线粒体中生物合成。先前的研究表明，线粒体 ABCB7 型外排泵参与细胞质铁硫蛋白的成熟。然而，ABCB7 型外排泵如何参与这一过程的分子机制仍不清楚。在这里，我们报告了一系列真核生物 CtAtm1 的冷冻电镜结构，其平均分辨率范围从 2.8 到 3.2 Å，并通过功能表征和分子对接进行了补充。我们提出 CtAtm1 接受来自谷胱甘肽结合的铁硫簇的递呈。部分封闭状态将货物结合与位于线粒体基质界面的残基连接起来，这些残基排列在线性正电荷腔内，而结合区域则内化，并在早期封闭状态下部分分离。总的来说，我们的发现大大提高了对真核 ABCB7 型蛋白运输机制的理解。
