The work of Sachin Katti, a graduate student in the Department of Biochemistry and Biophysics (Igumenova lab), was recently featured on the cover of Metallomics (Metallomics. 2018 Sep 19;10(9):1211-1222. doi: 10.1039/c8mt00135a). In this manuscript, the authors report structural, thermodynamic, and kinetic characterization of Pb(II) interactions with the calcium-sensing domain of Synaptotagmin 1. Synaptotagmin 1 is a key regulator of synaptic neurotransmission that was previously identified as a molecular target of Pb(II).
The major finding is that in addition to having thermodynamic advantage over Ca(II), Pb(II) possesses a kinetic advantage as well. Moreover, the population of high-affinity site by Pb(II) effectively desensitizes Synaptotagmin 1 to further Ca(II) interactions. This work provides structural and mechanistic insight into potential modes of Pb(II) toxicity and contributes to the fundamental understanding of biological chemistry of Pb(II), specifically its interactions with all-oxygen coordination sites in proteins. The results will assist in the identification of other Pb(II) targets, particularly C2-domain containing signaling proteins, and can potentially inform the design of Pb2+ sensors and possible antagonists.
Congratulations Sachin, on your discovery! It is such an honor that your work is featured as the cover of Mettallomics!