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Final Report Summary - METAL ION SENSORS (Determination of the sensing and transcription mechanisms of bacterial metal sensors using pulsed EPR)

Sharon Ruthstein is a senior lecturer (equivalent to assistant professor) in the Department of Chemistry, BIU, since October 2011. Her academic rank is a tenure track position. Sharon's main field is structural biology, where she is exploring the traffic mechanism of copper ions in bacterial and human cells. This is an extremely novel and exciting field, since the molecular-level pathways of copper ions in prokaryotic and eukaryotic cells is unknown. Copper ions are essential to the cells, however, in elevated concentrations these ions can be toxic. Hence, it is important to resolve each small step in the metal-ion cycle, in order to pre-diagnose sources that can interrupt the copper homeostasis. In this respect, electron paramagnetic resonance spectroscopy (EPR) is a powerful biophysical tool. EPR is not limited to the protein's size; rather, it is highly sensitive, and does not require crystallization. Thus, EPR can provide useful information on transient systems such as biological pathways. In the project, funded by the Marie Curie integration grant, Dr. Ruthstein's lab explores the transcription and detection mechanism of a class of proteins called metalloregulator proteins. These are metal sensor proteins that "sense" a specific metal ion by forming a specific coordination complex in a high affinity. This complex in turn, functions to either activate or inhibit DNA binding or transcription activation, and thereby controls the expression of genes that mediate an exquisitely selective adaptive response. To date, the lab has focused on the CueR copper metalloregulator protein, which is found in E.coli. Moreover, parallel to that, the lab has explored the efflux mechanism of Cu(I) ions in E.coli by the CusCBFA system. The lab succeeded in resolving the transcription mechanism of CueR, this resulted in comprehensive publication, which involved both experimental and computational part, and has recently been submitted to publication. As far as we know, this is the first time that a model is suggested from the point of view of the regulator to the transcription process of the MerR regulators.
In addition, the lab has succeeded to identify factors that control the Cu(I) efflux mechanism, results in one publication in Metallomics, and addition publication is now under consideration in Biochemistry.
Since copper is used also as antibacterial agent, the results obtained in this study are significant for the understanding pathogen's mechanism of survival and for the development of new and novel antibiotics.

The Marie Curie grant was also very helpful in establishing Sharon Ruthstein's research lab. In the last four years and a half since her appointment as a Senior Lecturer, Sharon has published nineteen papers. Sharon has also established several fruitful collaborations as a PI. One of these collaborations is with Prof. Haim Cohen (Ben Gurion University). This collaboration has resulted so far in four published papers, in all of which Dr. Ruthstein is one of the corresponding authors. In addition, Dr. Ruthstein explored the trafficking mechanism of heme in c.elegans, together with Prof. Iqbal Hamza (University of Maryland, USA), which has resulted in one publication so far. Dr. Ruthstein was invited to deliver several talks both abroad and in Israel, where she presented the research in her lab. Dr. Ruthstein was awarded an additional individual four-year grant by the ISF, a two years grant by the Israeli chief scientist, as well as new faculty equipment grant from the ISF. Last year Dr. Ruthstein was awarded the Krill prize from the Wolf foundation that is given each year for the best ten young scientists in Israel. Dr. Ruthstein's website is: www.ruthstein-lab.com.

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