Abstract
Friedreich's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.
Highlights
From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215 and the ʈDepartment of Internal Medicine 2, University of Cologne, Cologne 50931, Germany
Friedreich’s ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function
The structure of human frataxin, which we have determined at 1.8-Å resolution, reveals a novel protein fold
Summary
Sirano Dhe-Paganon‡, Ron Shigeta§, Young-In Chi¶, Michael Ristowʈ**, and Steven E. Friedreich’s ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin’s hydrophobic core. These structural findings predict potential modes of protein-protein and proteiniron binding. Yfh1p is cleaved by the mitochondrial processing protease to yield the mature, 122-amino acid active protein. We have determined the x-ray crystal structure of mature human frataxin to predict potential functions and to provide a framework for testing hypotheses
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