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STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF CHAPERONES IN FE-S CLUSTER BIOGENESIS AND REGULATION

Student thesis: Doctoral ThesisDoctor of Philosophy

Dysfunctions in Fe-S protein biogenesis and mitochondrial iron accumulation in heart and neurones are part of the phenotype of a genetic neurodegenerative disease called Friedreich's ataxia. This pathology is caused by the deficiency of a mitochondrial protein, frataxin, highly conserved throughout species and currently thought to be a regulator of Fe-S cluster biosynthesis. The study of the mechanism of Fe-S cluster assembly in mitochondria is important to provide insights and valuable information potentially relevant for the study of iron-storage diseases. The biogenesis of iron sulfur clusters involves a complex molecular machine with macromolecular structures containing multiple subunits with specific functions. The high level of conservation of the components suggests the bacterial system as excellent model because of its inherent lower complexity. Isc is one of the operons that encodes proteins responsible for Fe-S cluster biogenesis in bacteria, including the desulfurase IscS, the scaffold protein IscU on which the Fe-S cluster is assembled, the two chaperones HscA and HscB, the trascription regulator IscR, a ferredoxin and two other proteins called IscA and YfhJ, whose role is still unclear. The function of the chaperones HscA and HscB is thought to assist the transfer of the cluster from the scaffold protein to the final acceptors.
The main objective of this project was to get new evidence to understand the functions of the chaperones and the mechanisms by which they are involved in Fe-S cluster biogenesis and regulation through the application of structural biology and biochemistry. In particular, I focused on the structural and functional characterization of co-chaperone HscB and the analysis of its interactions with other members of the machinery through NMR and other biophysical techniques. My main findings are that HscB has an unprecedently reported interaction with IscS and that this interaction slows down cluster formation explaining a large plethora of evidence. These findings provide an entirely new perspective to the comprehension of the role of HscB and propose this protein as partner of central components of the Isc machine.
Original languageEnglish
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Award date2017

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