Mitochondria are complex, essential organelles of eucaryotic organisms required for a variety of metabolic processes, including energy generation by oxidative phosphorylation and iron metabolism. Pathological effects of reduced bioenergetic capacity and altered iron metabolism are common in human populations. Understanding the essential role of molecular chaperones within mitochondria in two conserved, essential physiological processes - translocation of proteins across mitochondrial membranes and the biogenesis of Fe/S clusters - is the long term goal of this project. Since the vast majority of the hundreds of mitochondrial proteins'are synthesized on cytosolic ribosomes, efficient protein import is critical. Protein import across the mitochindrial inner membrane is driven by an import motor associated with the inner membrane translocon, having at its core the mitochondrial matrix Hsp70, Ssc1. Similarly, a conserved cellular machinery present in the mitochondrial matrix is devoted to biogenesis of Fe/S clusters, essential moieties of proteins involved in a variety of diverse cellular process. As components of this machinery, the molecular chaperones Ssq1 and Jac1, Hsp70:J-protein partners, play a critical role through interaction with their substrate protein Isu, a scaffold on which an Fe/S cluster is assembled prior to transfer to a recipient apo-protein. Primarily using S. cerevisiae as a model system and bringing to bear a combination of genetic, biochemical and cell biological approaches, a goal of the proposed experiments is to gain an understand of these mitochondrial-specific physiological processes. The results of this research will also serve as a paradigm for understanding how molecular chaperones have diverged to function in diverse physiological functions, in addition to their well-established role in general protein folding, by evolving unique, regulated interactions with other cellular components, as well as making use of biochemical properties common to all Hsp70s.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Shapiro, Bert I
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
United States
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Craig, Elizabeth A (2018) Hsp70 at the membrane: driving protein translocation. BMC Biol 16:11
Schilke, Brenda A; Ciesielski, Szymon J; Ziegelhoffer, Thomas et al. (2017) Broadening the functionality of a J-protein/Hsp70 molecular chaperone system. PLoS Genet 13:e1007084
Dutkiewicz, Rafal; Nowak, Malgorzata; Craig, Elizabeth A et al. (2017) Fe-S Cluster Hsp70 Chaperones: The ATPase Cycle and Protein Interactions. Methods Enzymol 595:161-184
Ciesielski, Szymon J; Craig, Elizabeth A (2017) Posttranslational control of the scaffold for Fe-S cluster biogenesis as a compensatory regulatory mechanism. Curr Genet 63:51-56
Craig, Elizabeth A; Marszalek, Jaroslaw (2017) How Do J-Proteins Get Hsp70 to Do So Many Different Things? Trends Biochem Sci 42:355-368
Lee, Kanghyun; Sharma, Ruchika; Shrestha, Om Kumar et al. (2016) Dual interaction of the Hsp70 J-protein cochaperone Zuotin with the 40S and 60S ribosomal subunits. Nat Struct Mol Biol 23:1003-1010
Delewski, Wojciech; Paterkiewicz, Bogumi?a; Manicki, Mateusz et al. (2016) Iron-Sulfur Cluster Biogenesis Chaperones: Evidence for Emergence of Mutational Robustness of a Highly Specific Protein-Protein Interaction. Mol Biol Evol 33:643-56
Ciesielski, Szymon J; Schilke, Brenda; Marszalek, Jaroslaw et al. (2016) Protection of scaffold protein Isu from degradation by the Lon protease Pim1 as a component of Fe-S cluster biogenesis regulation. Mol Biol Cell 27:1060-8
Schmitz-Abe, Klaus; Ciesielski, Szymon J; Schmidt, Paul J et al. (2015) Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. Blood 126:2734-8
Yu, Hyun Young; Ziegelhoffer, Thomas; Craig, Elizabeth A (2015) Functionality of Class A and Class B J-protein co-chaperones with Hsp70. FEBS Lett 589:2825-30

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