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  1. Free, publicly-accessible full text available May 1, 2023
  2. Conserved homology 1 (C1) domains are peripheral zinc finger domains that are responsible for recruiting their host signaling proteins, including Protein Kinase C (PKC) isoenzymes, to diacylglycerol-containing lipid membranes. In this work, we investigated the reactivity of the C1 structural zinc sites, using the cysteine-rich C1B regulatory region of the PKCα isoform as a paradigm. The choice of Cd 2+ as a probe was prompted by previous findings that xenobiotic metal ions modulate PKC activity. Using solution NMR and UV-vis spectroscopy, we found that Cd 2+ spontaneously replaced Zn 2+ in both structural sites of the C1B domain, with the formation of all-Cd and mixed Zn/Cd protein species. The Cd 2+ substitution for Zn 2+ preserved the C1B fold and function, as probed by its ability to interact with a potent tumor-promoting agent. Both Cys 3 His metal-ion sites of C1B have higher affinity to Cd 2+ than Zn 2+ , but are thermodynamically and kinetically inequivalent with respect to the metal ion replacement, despite the identical coordination spheres. We find that even in the presence of the oxygen-rich sites presented by the neighboring peripheral membrane-binding C2 domain, the thiol-rich sites can successfully compete for the available Cd 2+ .more »Our results indicate that Cd 2+ can target the entire membrane-binding regulatory region of PKCs, and that the competition between the thiol- and oxygen-rich sites will likely determine the activation pattern of PKCs.« less
  3. Pb 2+ is a xenobiotic metal ion that competes for Ca 2+ -binding sites in proteins. Using the peripheral Ca 2+ -sensing domains of Syt1, we show that the chelating pH buffer Bis–Tris enables identification and functional characterization of high-affinity Pb 2+ sites that are likely to be targeted by bioavailable Pb 2+ .