Iron-Sulfur Cluster Assembly in Saccharomyces cerevisiae

1 Iron-Sulfur Cluster Assembly in Saccharomyces cerevisiae 

The current model for FeS cluster formation is based mainly on studies of S. cerevisiae, for which methods of genetic manipulation are well established (reviewed in Lill and Miihlenhoff 2005) (Fig. 6.3). The central pair of components of Fe cluster formation consist of mitochondrial IscS (Nfs), a pyridoxal phosphate-dependent desulfurase, and IscU (Isu), which serves as a scaffold for the formation of a transient FeS cluster. Sulfur released by IscS from cysteine is transferred to IscU and combined with iron to form a labile FeS 

During the transfer step of the FeS cluster from IscU to the target FeS apoproteins, the mitochondrial Hsp70 chaperone system, consisting of Flsp70 (Ssql), J-type cochaperone (Jacl), and nucleotide exchange factor (Mgel), is involved (Miihlenhoff et al. 2003 Dutkiewicz et al. 2003). 

In addition, IscA can perform similar functions to IscU, and under iron-limiting conditions can deliver iron to IscU (Ding et al. 2004). Nfu was proposed to serve as an alternative scaffold protein for FeS cluster assembly owing to its ability to bind labile FeS clusters (Schilke et al. 1999). Interestingly, both IscU and Nfu share homology with different domains of NifU, which functions in the specific assembly of nitrogenase FeS clusters as a part of the NIF system. 

Three cytosolic factors were recently characterized that contribute specifically to the maturation of cytosolic and nuclear FeS proteins. Cfdl (Roy et al. 2003) and Nbp35 (Hausmann et al. 2005) are essential soluble P-loop ATPases. Except for a short N-terminal extension in Nbp35 that itself carries an FeS cluster, these two proteins are structurally very similar. Together with the third component, yeast Narl (or human Narf, nuclear prelamin A recognition factor), these proteins have dual nuclear and cytosolic localization. It is not clear what the molecular role these cytosolic factors play in the maturation of FeS proteins is. An attractive hypothesis is that the FeS clusters or their precursors are transferred into the target apoproteins with the assistance of cytosolic factors after their export from mitochondria. Alternatively, the cytosolic proteins may facilitate de novo synthesis of FeS clusters in the cytosol using some compounds which are produced by mitochondrial FeS proteins (Lill and Miihlenhoff 2005). 

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