His86 from the N-terminus of Frataxin Coordinates Iron and is Required for Fe-S Cluster Synthesis

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2013 Aug 6

PMID 23909240

Citations 16

Authors

Leslie E Gentry

Matthew A Thacker

Reece Doughty

Russell Timkovich

Laura S Busenlehner

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Metal Ion Binding in Wild-Type and Mutated Frataxin: A Stability Study.

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Modelling Protein Plasticity: The Example of Frataxin and Its Variants.

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A Combined Spectroscopic and In Silico Approach to Evaluate the Interaction of Human Frataxin with Mitochondrial Superoxide Dismutase.

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