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Revision as of 14:04, 10 September 2016
proteopedia linkproteopedia linkArchitecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery: the Sub-Complex Formed by the Iron Donor, Yfh1, and the Scaffold, Isu1
Structural highlights
Function[ISU1_YEAST] Scaffold protein for the de novo synthesis of iron-sulfur (Fe-S) clusters within mitochondria, which is required for maturation of both mitochondrial and cytoplasmic [2Fe-2S] and [4Fe-4S] proteins. First, a [2Fe-2S] cluster is transiently assembled on the scaffold proteins ISU1 and ISU2. In a second step, the cluster is released from ISU1/ISU2, transferred to glutaredoxin GRX5, followed by the formation of mitochondrial [2Fe-2S] proteins, the synthesis of [4Fe-4S] clusters and their target-specific insertion into the recipient apoproteins. Cluster assembly on ISU1/ISU2 depends on the function of the cysteine desulfurase complex NFS1-ISD11, which serves as the sulfur donor for cluster synthesis, the iron-binding protein frataxin (YFH1) as the putative iron donor, and the electron transfer chain comprised of ferredoxin reductase ARH1 and ferredoxin YAH1, which receive their electrons from NADH. Fe-S cluster release from ISU1/ISU2 is achieved by interaction with the Hsp70 chaperone SSQ1, assisted by the DnaJ-like co-chaperone JAC1 and the nucleotide exchange factor MGE1. ISU1 is the major isoform in yeast, while ISU2 is not detectable in cells grown to stationary phase (PubMed:10588895, PubMed:12970193, PubMed:14741370, PubMed:15123690, PubMed:16341089, PubMed:16431909, PubMed:23615440, PubMed:25358379).[1] [2] [3] [4] [5] [6] [7] [8] [FRDA_YEAST] Promotes the biosynthesis of heme as well as the assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. Plays a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+). Can store large amounts of the metal in the form of a ferrihydrite mineral by oligomerization. May be involved in regulation of the mitochondrial electron transport chain.[9] [10] [11] [12] [13] [14] Publication Abstract from PubMedThe biosynthesis of Fe-S clusters is a vital process involving the delivery of elemental iron and sulfur to scaffold proteins via molecular interactions that are still poorly defined. We reconstituted a stable, functional complex consisting of the iron donor, Yfh1 (yeast frataxin homologue 1), and the Fe-S cluster scaffold, Isu1, with 1:1 stoichiometry, [Yfh1]24.[Isu1]24 Using negative staining transmission EM and single particle analysis, we obtained a three-dimensional reconstruction of this complex at a resolution of approximately 17 A. In addition, via chemical cross-linking, limited proteolysis, and mass spectrometry, we identified protein-protein interaction surfaces within the complex. The data together reveal that [Yfh1]24.[Isu1]24 is a roughly cubic macromolecule consisting of one symmetric Isu1 trimer binding on top of one symmetric Yfh1 trimer at each of its eight vertices. Furthermore, molecular modeling suggests that two subunits of the cysteine desulfurase, Nfs1, may bind symmetrically on top of two adjacent Isu1 trimers in a manner that creates two putative [2Fe-2S] cluster assembly centers. In each center, conserved amino acids known to be involved in sulfur and iron donation by Nfs1 and Yfh1, respectively, are in close proximity to the Fe-S cluster-coordinating residues of Isu1. We suggest that this architecture is suitable to ensure concerted and protected transfer of potentially toxic iron and sulfur atoms to Isu1 during Fe-S cluster assembly. Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery: THE SUB-COMPLEX FORMED BY THE IRON DONOR, Yfh1 PROTEIN, AND THE SCAFFOLD, Isu1 PROTEIN.,Ranatunga W, Gakh O, Galeano BK, Smith DY 4th, Soderberg CA, Al-Karadaghi S, Thompson JR, Isaya G J Biol Chem. 2016 May 6;291(19):10378-98. doi: 10.1074/jbc.M115.712414. Epub 2016, Mar 3. PMID:26941001[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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