Neuroscience

Enzyme

Cofactor

Cysteine

Iron-binding proteins

Ataxia

Biology

Gene

Epistemology

Philosophy

Function (biology)

Chemistry

Iron–sulfur cluster

Frataxin

Mechanism (biology)

Cell biology

Biochemistry

Proceedings of the National Academy of Sciences

Significance In humans, essential iron-sulfur (Fe-S) cluster cofactors are synthesized using an assembly complex that depends on the protein frataxin (FXN). The physiological function of FXN, which is linked to the fatal neurodegenerative disease Friedreich’s ataxia (FRDA), is still under debate. Here, we show that FXN accelerates Fe-S cluster formation by positioning a mobile loop cysteine of the assembly complex to interact with the substrate and function as an acid, nucleophile, and sulfur carrier during the reaction. Our architectural switch model suggests that FXN controls Fe-S cluster biosynthesis by inducing an unusual rearrangement of protein subunits in the assembly complex. These results provide mechanistic insights into this critical biological process and establish a foundation for the design of new FRDA treatments.

Mechanism of activation of the human cysteine desulfurase complex by frataxin