A pathway for assembling [4Fe-4S]2+ clusters in mitochondrial iron-sulfur protein biogenesis

Year: 2020

Authors: Nasta V., Suraci D., Gourdoupis S., Ciofi-Baffoni S., Banci L.

Autors Affiliation: Univ Florence, Magnet Resonance Ctr CERM, Via Luigi Sacconi 6, I-50019 Florence, Italy; Univ Florence, Dept Chem, Florence, Italy.

Abstract: During its late steps, the mitochondrial iron-sulfur cluster (ISC) assembly machinery leads to the formation of [4Fe-4S] clusters. In vivo studies revealed that several proteins are implicated in the biosynthesis and trafficking of [4Fe-4S] clusters in mitochondria. However, they do not provide a clear picture into how these proteins cooperate. Here, we showed that three late-acting components of the mitochondrial ISC assembly machinery (GLRX5, BOLA3, and NFU1) are part of a ISC assembly pathway leading to the synthesis of a [4Fe-4S](2+) cluster on NFU1. We showed that the [2Fe-2S](2+) GLRX5-BOLA3 complex transfers its cluster to monomeric apo NFU1 to form, in the presence of a reductant, a [4Fe-4S](2+) cluster bound to dimeric NFU1. The cluster formation on NFU1 does not occur with [2Fe-2S](2+) GLRX5, and thus, the [4Fe-4S] cluster assembly pathway is activated only in the presence of BOLA3. These results define NFU1 as an ’assembler’ of [4Fe-4S] clusters, that is, a protein able of converting two [2Fe-2S](2+) clusters into a [4Fe-4S](2+) cluster. Finally, we found that the [4Fe-4S](2+) cluster bound to NFU1 has a coordination site which is easily accessible to sulfur-containing ligands, as is typically observed in metallochaperones. This finding supports a role for NFU1 in promoting rapid and controlled cluster-exchange reaction.

Journal/Review: FEBS JOURNAL

Volume: 287 (11)      Pages from: 2312  to: 2327

More Information: The authors acknowledge the support and the use of resources of Instruct-ERIC, a Landmark ESFRI project, and specifically the CERM/CIRMMP Italy Centre. This article is based upon work from COST Action CA15133, supported by COST (European Cooperation in Science and Technology).
KeyWords: BOLA3; GLRX5; iron-sulfur protein; mitochondrial iron-sulfur cluster assembly machinery; NFU1
DOI: 10.1111/febs.15140