An unusual C2-domain in the active-zone protein piccolo: Implications for Ca2+ regulation of neurotransmitter release

Stefan H. Gerber, Jesus Garcia, Jose Rizo-Rey, Thomas C. Südhof

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Ca2+ regulation of neurotransmitter release is thought to require multiple Ca2+sensors with distinct affinities. However, no low-affinity Ca2+sensor has been identified at the synapse. We now show that piccolo/aczonin, a recently described active-zone protein with C-terminal C2A- and C2B-domains, constitutes a presynaptic low-affinity Ca2+sensor. Ca2+binds to piccolo by virtue of its C2A-domain via an unusual mechanism that involves a large conformational change. The distinct Ca2+-binding properties of the piccolo C2A-domain are mediated by an evolutionarily conserved sequence at the bottom of the C2A-domain, which may fold back towards the Ca2+-binding sites on the top. Point mutations in this bottom sequence inactivate it, transforming low-affinity Ca2+binding (100-200 μM in the presence of phospholipids) into high-affinity Ca2+binding (12-14 μM). The unusual Ca2+-binding mode of the piccolo C2A-domain reveals that C2-domains are mechanistically more versatile than previously envisaged. The low Ca2+affinity of the piccolo C2A-domain suggests that piccolo could function in short-term synaptic plasticity when Ca2+concentrations accumulate during repetitive stimulation.

Original languageEnglish (US)
Pages (from-to)1605-1619
Number of pages15
JournalEMBO Journal
Issue number7
StatePublished - Apr 2 2001


  • C-domain
  • Ca-binding protein
  • Exocytosis
  • Neurotransmitter release
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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