Anamorsin Is a [2Fe-2S] Cluster-Containing Substrate of the Mia40-Dependent Mitochondrial Protein Trapping Machinery

SummaryHuman anamorsin was implicated in cytosolic iron-sulfur (Fe/S) protein biogenesis. Here, the structural and metal-binding properties of anamorsin and its interaction with Mia40, a well-known oxidoreductase involved in protein trapping in the mitochondrial intermembrane space (IMS), were characterized. We show that (1), anamorsin contains two structurally independent domains connected by an unfolded linker; (2), the C-terminal domain binds a [2Fe-2S] cluster through a previously unknown cysteine binding motif in Fe/S proteins; (3), Mia40 specifically introduces two disulfide bonds in a twin CX2C motif of the C-terminal domain; (4), anamorsin and Mia40 interact through an intermolecular disulfide-bonded intermediate; and (5), anamorsin is imported into mitochondria. Hence, anamorsin is the first identified Fe/S protein imported into the IMS, raising the possibility that it plays a role in cytosolic Fe/S cluster biogenesis also once trapped in the IMS.

Graphical AbstractFigure optionsDownload high-quality image (237 K)Download as PowerPoint slideHighlights
► Anamorsin coordinates a [2Fe-2S] cluster in the C-terminal domain
► Anamorsin is imported into the IMS
► Anamorsin is a novel Mia40-substrate acquiring two S-S bonds in a twin CX2C motif
► Mia40-partnership suggests a role of IMS-imported anamorsin in Fe/S cluster biogenesis