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5t0v

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Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery: the Sub-Complex Formed by the Iron Donor, Yfh1, and the Scaffold, Isu1Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery: the Sub-Complex Formed by the Iron Donor, Yfh1, and the Scaffold, Isu1

Structural highlights

5t0v is a 48 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:ISU1, NUA1, YPL135W (ATCC 18824), YFH1, YDL120W (ATCC 18824)
Activity:Ferroxidase, with EC number 1.16.3.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

The 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

  1. ↑ Garland SA, Hoff K, Vickery LE, Culotta VC. Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family for iron-sulfur cluster assembly. J Mol Biol. 1999 Dec 10;294(4):897-907. PMID:10588895 doi:http://dx.doi.org/10.1006/jmbi.1999.3294
  2. ↑ Muhlenhoff U, Gerber J, Richhardt N, Lill R. Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p. EMBO J. 2003 Sep 15;22(18):4815-25. PMID:12970193 doi:http://dx.doi.org/10.1093/emboj/cdg446
  3. ↑ Ramazzotti A, Vanmansart V, Foury F. Mitochondrial functional interactions between frataxin and Isu1p, the iron-sulfur cluster scaffold protein, in Saccharomyces cerevisiae. FEBS Lett. 2004 Jan 16;557(1-3):215-20. PMID:14741370
  4. ↑ Dutkiewicz R, Schilke B, Cheng S, Knieszner H, Craig EA, Marszalek J. Sequence-specific interaction between mitochondrial Fe-S scaffold protein Isu and Hsp70 Ssq1 is essential for their in vivo function. J Biol Chem. 2004 Jul 9;279(28):29167-74. Epub 2004 Apr 30. PMID:15123690 doi:10.1074/jbc.M402947200
  5. ↑ Wiedemann N, Urzica E, Guiard B, Muller H, Lohaus C, Meyer HE, Ryan MT, Meisinger C, Muhlenhoff U, Lill R, Pfanner N. Essential role of Isd11 in mitochondrial iron-sulfur cluster synthesis on Isu scaffold proteins. EMBO J. 2006 Jan 11;25(1):184-95. Epub 2005 Dec 8. PMID:16341089 doi:http://dx.doi.org/10.1038/sj.emboj.7600906
  6. ↑ Dutkiewicz R, Marszalek J, Schilke B, Craig EA, Lill R, Muhlenhoff U. The Hsp70 chaperone Ssq1p is dispensable for iron-sulfur cluster formation on the scaffold protein Isu1p. J Biol Chem. 2006 Mar 24;281(12):7801-8. Epub 2006 Jan 23. PMID:16431909 doi:M513301200
  7. ↑ Uzarska MA, Dutkiewicz R, Freibert SA, Lill R, Muhlenhoff U. The mitochondrial Hsp70 chaperone Ssq1 facilitates Fe/S cluster transfer from Isu1 to Grx5 by complex formation. Mol Biol Cell. 2013 Jun;24(12):1830-41. doi: 10.1091/mbc.E12-09-0644. Epub 2013, Apr 24. PMID:23615440 doi:http://dx.doi.org/10.1091/mbc.E12-09-0644
  8. ↑ Webert H, Freibert SA, Gallo A, Heidenreich T, Linne U, Amlacher S, Hurt E, Muhlenhoff U, Banci L, Lill R. Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin. Nat Commun. 2014 Oct 31;5:5013. doi: 10.1038/ncomms6013. PMID:25358379 doi:http://dx.doi.org/10.1038/ncomms6013
  9. ↑ Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997 Jun 13;276(5319):1709-12. PMID:9180083
  10. ↑ Radisky DC, Babcock MC, Kaplan J. The yeast frataxin homologue mediates mitochondrial iron efflux. Evidence for a mitochondrial iron cycle. J Biol Chem. 1999 Feb 19;274(8):4497-9. PMID:9988680
  11. ↑ Gonzalez-Cabo P, Vazquez-Manrique RP, Garcia-Gimeno MA, Sanz P, Palau F. Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum Mol Genet. 2005 Aug 1;14(15):2091-8. Epub 2005 Jun 16. PMID:15961414 doi:10.1093/hmg/ddi214
  12. ↑ Gakh O, Park S, Liu G, Macomber L, Imlay JA, Ferreira GC, Isaya G. Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet. 2006 Feb 1;15(3):467-79. Epub 2005 Dec 21. PMID:16371422 doi:10.1093/hmg/ddi461
  13. ↑ Leidgens S, De Smet S, Foury F. Frataxin interacts with Isu1 through a conserved tryptophan in its beta-sheet. Hum Mol Genet. 2010 Jan 15;19(2):276-86. Epub 2009 Nov 2. PMID:19884169 doi:ddp495
  14. ↑ Karlberg T, Schagerlof U, Gakh O, Park S, Ryde U, Lindahl M, Leath K, Garman E, Isaya G, Al-Karadaghi S. The structures of frataxin oligomers reveal the mechanism for the delivery and detoxification of iron. Structure. 2006 Oct;14(10):1535-46. PMID:17027502 doi:10.1016/j.str.2006.08.010
  15. ↑ Ranatunga W, Gakh O, Galeano BK, Smith DY 4th, Soderberg CA, Al-Karadaghi S, Thompson JR, Isaya G. 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. J Biol Chem. 2016 May 6;291(19):10378-98. doi: 10.1074/jbc.M115.712414. Epub 2016, Mar 3. PMID:26941001 doi:http://dx.doi.org/10.1074/jbc.M115.712414

5t0v, resolution 17.50Å

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