5vfe
Synaptotagmin 1 C2A domain, lead-bound
Structural highlights
FunctionSYT1_MOUSE May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (PubMed:7961887). It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. Plays a role in dendrite formation by melanocytes (By similarity).[UniProtKB:P21579][1] Publication Abstract from PubMedLead (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. High affinity interactions of Pb(2+) with synaptotagmin I.,Katti S, Her B, Srivastava AK, Taylor AB, Lockless SW, Igumenova TI Metallomics. 2018 Sep 19;10(9):1211-1222. doi: 10.1039/c8mt00135a. PMID:30063057[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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