The ubiquitous mitochondrial J-protein Jac1, called HscB in Escherichia coli, and its partner Hsp70 play a critical role in the transfer of Fe-S clusters from the scaffold protein Isu to recipient proteins. Biochemical results from eukaryotic and prokaryotic systems indicate that formation of the Jac1-Isu complex is important for both targeting of the Isu for Hsp70 binding and stimulation of Hsp70’s ATPase activity. However, in apparent contradiction, we previously reported that an 8 fold decrease in Jac1’s affinity for Isu1 is well tolerated in vivo, raising the question as to whether the Jac1:Isu interaction actually plays an important biological role. Here we report the determination of the structure of Jac1 from Saccharomyces cerevisiae. Taking advantage of this information and recently published data from the homologous bacterial system, a total of eight surface exposed residues were determined to play a role in Isu binding, as assessed by a set of biochemical assays. A variant having alanines substituted for these eight residues was unable to support growth of a jac1-Δ strain. However, replacement of three residues caused partial loss of function, resulting in a significant decrease in the Jac1:Isu1 interaction, a slow growth phenotype and a reduction in the activity of Fe-S cluster containing enzymes. Thus, we conclude that the Jac1:Isu1 interaction plays an indispensible role in the essential process of mitochondrial Fe-S cluster biogenesis.
Background: Little is known regarding the dynamics of the interaction of proteins with the Fe/S cluster scaffold Isu1. Results: Three conserved Isu1 residues are critical for interaction with cysteine desulfurase Nfs1 and J-protein cochaperone Jac1, required for cluster assembly and transfer, respectively. Conclusion: Jac1 and Nfs1 binding to Isu1 are mutually exclusive. Significance: Mutual exclusivity suggests a point of regulation of the cluster assembly/transfer cycle.
Background: Protein factors function in both FeS cluster assembly on and transfer from the Isu scaffold protein.Results: Common Isu residues are critical for binding both frataxin homologue (Yfh1) assembly factor and heat shock protein 70 (Hsp70) transfer factor. Conclusion: Yfh1 and Hsp70 binding is mutually exclusive. Significance: Mutual exclusive binding of assembly/transfer factors may be important in transitioning between cluster assembly and transfer.
This article reports metabolic consequences of JAK2-mutant myeloproliferative neoplasms (MPNs) with a therapeutic translational impact: expression of mutant JAK2 induces abnormal metabolic activity of MPN cells, resulting in hypoglycemia, adipose tissue atrophy, and early mortality.
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