Fig. 7: Mechanistic working model for the reaction cycle of [2Fe-2S] cluster formation on an ISCU2 dimer by the mitochondrial core ISC complex.
From: N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization
For simplicity, only one half of the symmetrical core ISC complex (green box, upper right) is shown in the reaction cycle. The steps are: 1. A persulfide is generated in a PLP-dependent fashion on a flexible Cys-containing loop of NFS1 (as part of the (NIA)2 complex). 2. Upon binding of Fe-loaded ISCU2 and FXN to NFS1, the persulfide is rapidly transferred from NFS1 to an active-site Cys of ISCU2. 3. Binding of reduced FDX2 assists the reduction of persulfide sulfur to sulfide (˗). 4. Tyr35-mediated dimerization of two (Fe and S ion-binding) ISCU2 proteins on different core ISC complexes yields a bridging [2Fe-2S] cluster on an ISCU2 dimer. 5. Finally, the [2Fe-2S] cluster is further transferred to glutaredoxin 5 (GLRX5) in chaperone-dependent fashion, and (NIA)2, FXN, oxidized FDX2, and apo-ISCU2 are recycled for the next synthesis round. Red and yellow circles, iron and sulfur; Y, Tyr35; e-, reducing electron on FDX2.
