Characteristics of the Isu1 C-terminus in relation to [2Fe-2S] cluster assembly and ISCU Myopathy

JBIC Journal of Biological Inorganic Chemistry - Tập 27 - Trang 759-773 - 2022
Brianne E. Lewis1, Courtney J. Campbell2, Andria Rodrigues2, Lindsey Thompson2, Ashutosh K. Pandey3, Sarah N. Gallagher2, Debkumar Pain3, Andrew Dancis4, Timothy L. Stemmler2
1Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, USA
2Department of Pharmaceutical Science, Wayne State University, Detroit, USA
3Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, USA
4Division of Hematology-Oncology, Perelman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, USA

Tóm tắt

Mitochondrial [2Fe-2S] cluster biosynthesis is driven by the coordinated activities of the Iron–Sulfur Cluster (ISC) pathway protein machinery. Within the ISC machinery, the protein that provides a structural scaffold on which [2Fe-2S] clusters are assembled is the ISCU protein in humans; this protein is referred to as the “Scaffold” protein. Truncation of the C-terminal portion of ISCU causes the fatal disease “ISCU Myopathy”, which exhibits phenotypes of reduced Fe-S cluster assembly in cells. In this report, the yeast ISCU ortholog “Isu1” has been characterized to gain a better understanding of the role of the scaffold protein in relation to [2Fe-2S] assembly and ISCU Myopathy. Here we explored the biophysical characteristics of the C-terminal region of Isu1, the segment of the protein that is truncated on the human ortholog during the disease ISCU Myopathy. We characterized the role of this region in relation to iron binding, protein stability, assembly of the ISC multiprotein complex required to accomplish Fe-S cluster assembly, and finally on overall cell viability. We determined the Isu1 C-terminus is essential for the completion of the Fe-S cluster assembly but serves a function independent of protein iron binding.

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