High affinity interactions of Pb 2+ with synaptotagmin I

Sachin Katti, Bin Her, Atul K. Srivastava, Alexander B. Taylor, Steve W. Lockless, Tatyana I. Igumenova

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Lead (Pb) is a potent neurotoxin that disrupts synaptic neurotransmission. We report that Synaptotagmin I (SytI), a key regulator of Ca 2+ -evoked neurotransmitter release, has two high-affinity Pb 2+ binding sites that belong to its cytosolic C2A and C2B domains. The crystal structures of Pb 2+ -complexed C2 domains revealed that protein-bound Pb 2+ ions have holodirected coordination geometries and all-oxygen coordination spheres. The on-rate constants of Pb 2+ binding to the C2 domains of SytI are comparable to those of Ca 2+ and are diffusion-limited. In contrast, the off-rate constants are at least two orders of magnitude smaller, indicating that Pb 2+ can serve as both a thermodynamic and kinetic trap for the C2 domains. We demonstrate, using NMR spectroscopy, that population of these sites by Pb 2+ ions inhibits further Ca 2+ 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 Pb 2+ ions can interfere with the Ca 2+ -dependent function of SytI in the cell.

Original languageEnglish (US)
Pages (from-to)1211-1222
Number of pages12
JournalMetallomics
Volume10
Issue number9
DOIs
StatePublished - Sep 2018

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Biophysics
  • Biomaterials
  • Biochemistry
  • Metals and Alloys

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