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Metallomics. 2018 Sep 19;10(9):1211-1222. doi: 10.1039/c8mt00135a.

High affinity interactions of Pb2+ with synaptotagmin I.

Author information

1
Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard, College Station, TX 77843, USA. tigumenova@tamu.edu.

Abstract

Lead (Pb) is a potent neurotoxin that disrupts synaptic neurotransmission. We report that Synaptotagmin I (SytI), a key regulator of Ca2+-evoked neurotransmitter release, has two high-affinity Pb2+ binding sites that belong to its cytosolic C2A and C2B domains. The crystal structures of Pb2+-complexed C2 domains revealed that protein-bound Pb2+ ions have holodirected coordination geometries and all-oxygen coordination spheres. The on-rate constants of Pb2+ binding to the C2 domains of SytI are comparable to those of Ca2+ and are diffusion-limited. In contrast, the off-rate constants are at least two orders of magnitude smaller, indicating that Pb2+ can serve as both a thermodynamic and kinetic trap for the C2 domains. We demonstrate, using NMR spectroscopy, that population of these sites by Pb2+ ions inhibits further Ca2+ binding despite the existing coordination vacancies. Our work offers a unique insight into the bioinorganic chemistry of Pb(ii) and suggests a mechanism by which low concentrations of Pb2+ ions can interfere with the Ca2+-dependent function of SytI in the cell.

PMID:
30063057
PMCID:
PMC6146066
[Available on 2019-09-19]
DOI:
10.1039/c8mt00135a

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