Evolution of Mitochondrial Chaperones Utilized in Fe-S Cluster Biogenesis

Abstract

Biogenesis of Fe-S clusters is an essential process [1]. In both Escherichia coli and Saccharomyces cerevisiae, insertion of clusters into an apoprotein requires interaction between a scaffold protein on which clusters are assembled and a molecular chaperone system--an unusually specialized mitochondrial Hsp70 (mtHsp70) and its J protein cochaperone [2]. It is generally assumed that mitochondria inherited their Fe-S cluster assembly machinery from prokaryotes via the endosymbiosis of a bacterium that led to formation of mitochondria. Indeed, phylogenetic analyses demonstrated that the S. cerevisiae J protein, Jac1, and the scaffold, Isu, are orthologous to their bacterial counterparts [3, 4]. However, our analyses indicate that the specialized mtHsp70, Ssq1, is only present in a subset of fungi; most eukaryotes have a single mtHsp70, Ssc1. We propose that an Hsp70 having a role limited to Fe-S cluster biogenesis arose twice during evolution. In the fungal lineage, the gene encoding multifunctional mtHsp70, Ssc1, was duplicated, giving rise to specialized Ssq1. Therefore, Ssq1 is not orthologous to the specialized Hsp70 from E. coli (HscA), but shares a striking level of convergence at the biochemical level. Thus, in the vast majority of eukaryotes, Jac1 and Isu function with the single, multifunctional mtHsp70 in Fe-S cluster biogenesis.

The Human Escort Protein Hep Binds to the ATPase Domain of Mitochondrial Hsp70 and Regulates ATP Hydrolysis

“…In contrast, a chimera having the mtHsp70 PBD fused to an HscA ATPase domain was completely soluble upon overexpression in E. coli. These findings are consistent with studies performed by Craig and coworkers (2), which showed that an mtHsp70 truncation mutant having ATPase , ⌬v is the observed change in rate, and ⌬v max is the maximal rate obtained by extrapolating to infinite Hep concentration. The data are fit to a hyperbolic saturation function assuming a maximal stimulation for 70…”

Mitochondrial protein homeostasis

“…The representative of all major families such as Hsp70 and its co-chaperones, Hsp60 and Hsp100 (Hsp78 in mitochondria), are represented and they display a broad specificity. However, more specialized chaperones such as those acting in the iron-sulfur cluster assembly pathway are also known (89,90). It is less clear how proteins in the IMS are folded and assembled into the functional units.…”

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

“…2). The dissociation of the Fe/S cluster from Isu1 is facilitated by a dedicated Hsp70 chaperone system comprised of the Hsp70 ATPase Ssq1 (human mortalin), the DnaJ-like cochaperone Jac1 (human Hsc20), and the nucleotide exchange factor Mge1 (human GRPE-L1/2) (Schilke et al 2006;Vickery and Cupp-Vickery 2007;Uhrigshardt et al 2010). The molecular mechanism of the chaperones in this reaction is strikingly similar to Hsp70 chaperone function in protein folding, and has been worked out in both bacteria and yeast (Vickery and Cupp-Vickery 2007;Kampinga and Craig 2010).…”