John Zuris
Former Lab Member
Recently accepted a posdoc position with David Liu at Harvard University
Research Description
I perform structural and functional characterizations of mitoNEET and NAF-1, two members of the CDGSH family of [2Fe-2S] proteins. I am attempting to elcidate their still emerging, but important role, in oxidative stress and type II diabetes. MitoNEET is a recently discovered redox active [2Fe-2S] protein tethered to the outer mitochondrial membrane. It is a known target of the anti-diabetes drug pioglitazone. My project was to understand the function of mitoNEET’s [2Fe-2S] cluster and determine how pioglitazone modulates cluster properties. I found that both mitoNEET’s redox and cluster transfer properties are modulated significantly by NADPH as well as the anti-diabetes drug pioglitazone. NAF-1, which is tethered to both the outer-mitochondrial membrane and the endoplasmic reticulum, has yielded similar findings.
In my second project I used a rational design approach to performed point mutagenesis on mitoNEET in order to engineer the redox potential of mitoNEET’s [2Fe-2S] center to span ~700 mV, the largest range ever engineered in an FeS protein. This wide range in redox potential suggests that mitoNEET could be useful as a mediator for multistep electron transfer processes such as that in fuel cells.
In addition to the my studies on CDGSH proteins, I also used protein-film voltammetry to show that mutation of specific residues in a loop region far from the [2Fe-2S] redox center in ferredoxin unexpectedly led to changes in the protein’s electron transfer properties. This work gave crucial experimental evidence to computational work that had suggested a possible communication between this loop region and the metal center. We hope to investigate whether long-range effects can influence the cluster properties of the CDGSH family of proteins as well.
Publications:
Zuris, J. A.; Ali, S. S.; Yeh, H.; Nguyen, T. A.; Nechushtai, R.; Paddock, M. L.; Jennings, P. A., NADPH Inhibits 2Fe-2S Cluster Protein Transfer from Diabetes Drug Target MitoNEET to an Apo-acceptor Protein. Journal of Biological Chemistry 2012, 287 (15), 11649-11655;
Nechushtai, R.; Lammert, H.; Michaeli, D.; Eisenberg-Domovich, Y.; Zuris, J. A.; Luca, M. A.; Capraro, D. T.; Fish, A.; Shimshon, O.; Roy, M.; Schug, A.; Whitford, P. C.; Livnah, O.; Onuchic, J. N.; Jennings, P. A., Allostery in the ferredoxin protein motif does not involve a conformational switch. Proceedings of the National Academy of Sciences of the United States of America 2011, 108 (6), 2240-2245;
Zuris, J. A.; Harir, Y.; Conlan, A. R.; Shvartsman, M.; Michaeli, D.; Tamir, S.; Paddock, M. L.; Onuchic, J. N.; Mittler, R.; Cabantchik, Z. I.; Jennings, P. A.; Nechushtai, R., Facile transfer of 2Fe-2S clusters from the diabetes drug target mitoNEET to an apo-acceptor protein. Proceedings of the National Academy of Sciences of the United States of America 2011, 108 (32), 13047-13052;
Zuris, J. A.; Halim, D. A.; Conlan, A. R.; Abresch, E. C.; Nechushtai, R.; Paddock, M. L.; Jennings, P. A., Engineering the Redox Potential over a Wide Range within a New Class of FeS Proteins. Journal of the American Chemical Society 2010, 132 (38), 13120-13122;
Bak, D. W.; Zuris, J. A.; Paddock, M. L.; Jennings, P. A.; Elliott, S. J., Redox Characterization of the FeS Protein MitoNEET and Impact of Thiazolidinedione Drug Binding. Biochemistry 2009, 48 (43), 10193-10195;
Conlan, A. R.; Axelrod, H. L.; Cohen, A. E.; Abresch, E. C.; Zuris, J.; Yee, D.; Nechushtai, R.; Jennings, P. A.; Paddock, M. L., Crystal Structure of Miner1: The Redox-active 2Fe-2S Protein Causative in Wolfram Syndrome 2. Journal of Molecular Biology 2009, 392 (1), 143-153;