Thursday, February 15, 2018

Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly

Kai Cai. Volume 114, Issue 3, Supplement 1, 2 February 2018, Pages 571a, doi:10.1016/j.bpj.2017.11.3123

Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.

 Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly