In recent years the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focus of major studies. This is partly because of its high relevance in cell metabolism, but also because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was solved at 2.0 Å resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds and also by apolar interactions. The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the core complex NFS1/ACP-ISD11 was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamic simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to the one found in the context of the supercomplex core (NFS1/ACP-ISD11)2, which contains the E. coli ACP instead of the human variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11 complex may fold independently and after that, the NFS1 dimer is stabilized.
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