Rxivist logo

High affinity interactions of Pb2+ with Synaptotagmin I

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

Posted 16 Jun 2018
bioRxiv DOI: 10.1101/348748 (published DOI: 10.1039/c8mt00135a)

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 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.

Download data

  • Downloaded 210 times
  • Download rankings, all-time:
    • Site-wide: 69,565 out of 92,290
    • In biophysics: 3,021 out of 4,010
  • Year to date:
    • Site-wide: 80,452 out of 92,290
  • Since beginning of last month:
    • Site-wide: 62,673 out of 92,290

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News