| Structural highlights
5tre 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
Early studies of the bacterial Fe-S cluster assembly system provided structural details for how the scaffold protein and the cysteine desulfurase interact. This work and additional work on the yeast and human systems elucidated a conserved mechanism for sulfur donation but did not provide any conclusive insights into the mechanism for iron delivery from the iron donor, frataxin, to the scaffold. We previously showed that oligomerization is a mechanism by which yeast frataxin (Yfh1) can promote assembly of the core machinery for Fe-S cluster synthesis both in vitro and in cells, in such a manner that the scaffold protein, Isu1, can bind to Yfh1 independent of the presence of the cysteine desulfurase, Nfs1. Here, in the absence of Yfh1, Isu1 was found to exist in two forms, one mostly monomeric with limited tendency to dimerize, and one with a strong propensity to oligomerize. Whereas the monomeric form is stabilized by zinc, the loss of zinc promotes formation of dimer and higher order oligomers. However, upon binding to oligomeric Yfh1, both forms take on a similar symmetrical trimeric configuration that places the Fe-S cluster coordinating residues of Isu1 in close proximity of iron-binding residues of Yfh1. This configuration is suitable for docking of Nfs1 in a manner that provides a structural context for coordinate iron and sulfur donation to the scaffold. Moreover, distinct structural features suggest that in physiological conditions the zinc-regulated abundance of monomeric vs. oligomeric Isu1 yields [Yfh1].[Isu1] complexes with different Isu1 configurations that afford unique functional properties for Fe-S cluster assembly and delivery.
Zinc and the iron donor frataxin regulate oligomerization of the scaffold protein to form new Fe-S cluster assembly centers.,Galeano BK, Ranatunga W, Gakh O, Smith DY, Thompson JR, Isaya G Metallomics. 2017 Jun 21;9(6):773-801. doi: 10.1039/c7mt00089h. PMID:28548666[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Galeano BK, Ranatunga W, Gakh O, Smith DY, Thompson JR, Isaya G. Zinc and the iron donor frataxin regulate oligomerization of the scaffold protein to form new Fe-S cluster assembly centers. Metallomics. 2017 Jun 21;9(6):773-801. doi: 10.1039/c7mt00089h. PMID:28548666 doi:http://dx.doi.org/10.1039/c7mt00089h
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