The Structure of the Human ACP- ISD11 Heterodimer

HERRERA, M.G; AGUDELO SUÁREZ, WILLIAM ARMANDO; SANTOS, JAVIER; NOGUERA, MARTÍN E.; KLINKE, SEBASTIÁN; SEWELL, KARL ELLIOTH; CAPECE, LUCIANA

Washington

Congreso; International Ataxia Research Congress; 2019

In recent years the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focusof major studies. This is partly because of its high relevance in cell metabolism, but also because mutations ofthe involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme ofthe complex and the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure ofthe human mitochondrial ACP-ISD11 heterodimer was solved at 2.0 Å resolution. ACP-ISD11 forms a cooperativeunit. The 4?-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues ofISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 interacted with theNFS1 desulfurase, thus yielding an active enzyme, and the core complex NFS1/ACP-ISD11 was activated by frataxinand ISCU proteins. Motions of ACP-ISD11 dimer were investigated by molecular dynamics simulations, showingthe persistence of the interactions between both protein chains. The conformation of the dimer is similar to theone found in the context of the supercomplex core (NFS1/ACP-ISD11)2, which contains the E. coli ACP instead of thehuman variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11complex may fold independently and after that, the NFS1 dimer is stabilized.