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The iron-sulfur cluster assembly (ISC) protein Iba57 executes a tetrahydrofolate-independent function in mitochondrial [4Fe-4S] protein maturation
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Mühlenhoff, Ulrich, Weiler, Benjamin Dennis, Nadler, Franziska, Millar, Robert, Kothe, Isabell, Freibert, Sven-Andreas, Altegoer, Florian, Bange, Gert and Lill, Roland (2022) The iron-sulfur cluster assembly (ISC) protein Iba57 executes a tetrahydrofolate-independent function in mitochondrial [4Fe-4S] protein maturation. Journal of Biological Chemistry, 298 (10). 102465. doi:10.1016/j.jbc.2022.102465 ISSN 0021-9258.
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WRAP-The-iron-sulfur-cluster-assembly-ISC-protein-Iba57-executes-a-tetrahydrofolate-independent-function-Millar-2022.pdf - Accepted Version Embargoed item. Restricted access to Repository staff only - Requires a PDF viewer. Download (19Mb) |
Official URL: http://dx.doi.org/10.1016/j.jbc.2022.102465
Abstract
Mitochondria harbor the bacteria-inherited iron-sulfur cluster assembly (ISC) machinery to generate [2Fe-2S] and [4Fe-4S] proteins. In yeast, assembly of [4Fe-4S] proteins specifically involves the ISC proteins Isa1, Isa2, Iba57, Bol3, and Nfu1. Functional defects in their human equivalents cause the multiple mitochondrial dysfunction syndromes (MMDS), severe disorders with a broad clinical spectrum. The bacterial Iba57 ancestor YgfZ was described to require tetrahydrofolate (THF) for its function in the maturation of selected [4Fe-4S] proteins. Both YgfZ and Iba57 are structurally related to an enzyme family catalyzing THF-dependent one-carbon transfer reactions including GcvT of the glycine cleavage system. On this basis, a universally conserved folate requirement in ISC-dependent [4Fe-4S] protein biogenesis was proposed. To test this idea for mitochondrial Iba57, we performed genetic and biochemical studies in S. cerevisiae, and we solved the crystal structure of Iba57 from the thermophilic fungus Chaetomium thermophilum. We provide three lines of evidence for the THF independence of the Iba57-catalyzed [4Fe-4S] protein assembly pathway. First, yeast mutants lacking folate show no defect in mitochondrial [4Fe-4S] protein maturation. Second, the 3D structure of Iba57 lacks many of the side chain contacts to THF as defined in GcvT, and the THF binding pocket is constricted. Third, mutations in conserved Iba57 residues that are essential for THF-dependent catalysis in GcvT do not impair Iba57 function in vivo, in contrast to an exchange of the invariant, surface-exposed cysteine residue. We conclude that mitochondrial Iba57, despite structural similarities to both YgfZ and THF-binding proteins, does not utilize folate for its function.
Item Type: | Journal Article | ||||||||||||
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Subjects: | Q Science > QD Chemistry Q Science > QH Natural history Q Science > QP Physiology R Medicine > RB Pathology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||
Library of Congress Subject Headings (LCSH): | Iron-sulfur proteins , Folic acid, Crystallography , Mitochondria, Mitochondrial pathology | ||||||||||||
Journal or Publication Title: | Journal of Biological Chemistry | ||||||||||||
Publisher: | American Society for Biochemistry and Molecular Biology | ||||||||||||
ISSN: | 0021-9258 | ||||||||||||
Official Date: | October 2022 | ||||||||||||
Dates: |
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Volume: | 298 | ||||||||||||
Number: | 10 | ||||||||||||
Article Number: | 102465 | ||||||||||||
DOI: | 10.1016/j.jbc.2022.102465 | ||||||||||||
Status: | Peer Reviewed | ||||||||||||
Publication Status: | Published | ||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||
Date of first compliant deposit: | 5 October 2022 | ||||||||||||
Date of first compliant Open Access: | 6 October 2022 | ||||||||||||
RIOXX Funder/Project Grant: |
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