NSF-BSF: Novel determinants of prokaryotic copper homeostasis

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Metals are essential nutrients for all life forms. In particular, copper plays a role in respiration and antioxidant defense. However, too much copper is toxic and can damage cells. Therefore, specific proteins are used to bind copper and carry it to different cellular locations. Since metals are present in one third of all proteins, studying their transport and delivery is of fundamental importance and impacts understanding of many biological and environmental processes, including global element cycles. The goal of this project is to investigate how bacteria obtain and distribute copper. The project will provide opportunities for interdisciplinary research training at all levels as well as for mentoring and outreach in the local community. Moreover, the project will present a unique opportunity for scientists from the US and Israel to work closely together, leading to expanded skillsets and experiences with diverse scientific communities and ways of conducting research. Such exposure is an essential component of training scientists in an increasingly global society.Since prokaryotic copper enzymes are extracytoplasmic, most research has addressed either copper import to the periplasm for enzyme loading or mechanisms of copper resistance, with little focus on the possibility of controlled cytoplasmic copper import. Nevertheless, growing evidence suggests that import to the cytoplasm may be required for loading of some periplasmic copper enzymes. Putative cytoplasmic copper importers include members of the CopD/YcnJ/YebZ family of transmembrane proteins. Genes encoding these proteins are typically found associated with genes encoding periplasmic copper binding proteins, such as CopCs and other yet-to-be characterized proteins. This project will investigate both periplasmic and transmembrane proteins implicated in cyotplasmic copper import, focusing primarily on systems found in E. coli. The approach combines genetic, computational, biophysical, and structural methods that leverage the complementary expertises of the collaborating laboratories in the US and Israel. The research will result in elucidation of the structure and function of previously uncharacterized copper-binding proteins and will lead to new models of bacterial copper homeostasis.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.