Protein-Interaction Affinity Gradient Drives [4Fe-4S] ClusterInsertion in Human Lipoyl Synthase

Human lipoyl synthase (LIAS) is an enzyme containing two [4Fe-4S] clusters (named FeSRSand FeSaux) involved inthe biosynthesis of the lipoyl cofactor. The mechanism by which a [4Fe-4S] cluster is inserted into LIAS has thus far remainedelusive. Here we show that NFU1 and ISCA1 of the mitochondrial iron-sulfur cluster assembly machinery, via forming aheterodimeric complex, are the key factors for the insertion of a [4Fe-4S] cluster into the FeSRSsite of LIAS. In this process, thecrucial actor is the C-domain of NFU1, which, by exploiting a protein-interaction affinity gradient increasing from ISCA1 to LIAS,drives the cluster to itsfinal destination.

Automated summary

In this study, it was discovered that NFU1 and ISCA1 in the mitochondrial iron-sulfur cluster assembly machinery play a crucial role in the insertion of a [4Fe-4S] cluster into LIAS by forming a heterodimeric complex. The C-domain of NFU1 drives the cluster to its final destination by exploiting a protein interaction affinity gradient.