1 research outputs found
His86 from the N‑Terminus of Frataxin Coordinates Iron and Is Required for Fe–S Cluster Synthesis
Human
frataxin has a vital role in the biosynthesis of iron–sulfur
(Fe–S) clusters in mitochondria, and its deficiency causes
the neurodegenerative disease Friedreich’s ataxia. Proposed
functions for frataxin in the Fe–S pathway include iron donation
to the Fe–S cluster machinery and regulation of cysteine desulfurase
activity to control the rate of Fe–S production, although further
molecular detail is required to distinguish these two possibilities.
It is well established that frataxin can coordinate iron using glutamate
and aspartate side chains on the protein surface; however, in this
work we identify a new iron coordinating residue in the N-terminus
of human frataxin using complementary spectroscopic and structural
approaches. Further, we demonstrate that His86 in this N-terminal
region is required for high affinity iron coordination and iron assembly
of Fe–S clusters by ISCU as part of the Fe–S cluster
biosynthetic complex. If a binding site that includes His86 is important
for Fe–S cluster synthesis as part of its chaperone function,
this raises the possibility that either iron binding at the acidic
surface of frataxin may be spurious or that it is required for protein–protein
interactions with the Fe–S biosynthetic quaternary complex.
Our data suggest that iron coordination to frataxin may be significant
to the Fe–S cluster biosynthesis pathway in mitochondria