Structural and sequence basis for substrate selection in the cellular trafficking of Fe-S clusters, hemes and glutathione-complexed metals through membrane transporters

Cellular mobilization of heme and iron‑sulfur cluster cofactors has been a topic of interest for over a decade. Recognition of glutathione-complexed clusters as viable mediators of intracellular trafficking of [2Fe-2S] cofactors and other metallosubstrates for transmembrane localization has been demonstrated both biochemically and by structural studies, and is supported by genetic analysis. Sequence and structural correlations of both eukaryotic and prokaryotic ATP-binding cassette (ABC) membrane transporter families (ABCB7 and ABCB6) reveals connections that address possible roles for ABCB6 in Fe-S cluster cellular mobilization and further clarify its role in heme transport. This review expands on these themes by correlating structural and sequence relationships between Fe-S cluster and heme transporters, and broader roles in mediating drug resistance and elimination of toxic metals.