Structure of the human Fe–S cluster assembly sub-complex: implications in Friedreich's ataxia and primary metabolism
Year: 2018
Type: article
Abstract: Iron-sulfur (Fe-S) clusters are small, inorganic cofactors required for most living organisms. 1hese cofactors play roles in many essential processes including oxidative respiration and DNA replication and repair.In eukaryotes, Fe-S clusters are synthesized and distributed in the mitochondria by a multi-protein complex.A tightly bound sub-complex of this system consists of the cysteine desulfurase, NFS1, and essential eukaryotic specific adaptor proteins ISD11 and acylcarrier protein (ACP).This sub-complex catalyzes the conversion of cysteine to alanine and persulfide sulfur.This persulfide sulfur can be transferred to the scaffold protein, ISCU2, where in the presence of Fe 2+ and electrons, a [2Fe-2S] cluster can be formed.2][3][4] In order to elucidate mechanistic details which lead to the activation properties of FXN, we determined 3.09 Å x-ray crystal and 15 Å electron microscopy structures of the sub-complex consisting of human NFS-ISD11 in complex with ACP from E. coli.Along with in vitro characterization, we also conducted mutagenesis studies on the NFS1-ISD11-ACP sub-complex in S. cerevisiae in order to validate interaction surfaces.Overall, this structure reveals a new architecture for cysteine desulfurases that clearly demonstrates the essential nature of ISD11 and ACP in Fe-S cluster biosynthesis and provides a mechanistic hypothesis for FXN based activation.In addition, we also demonstrate that ACP threads its lipid-bound cofactor into ISD11 generating new links among Fe-S cluster biosynthesis, primary metabolism, and mitochondrial fatty-acid synthesis. 5
Language: English
Field: Energy
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W2914065671