Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4

Han Dai, Ok Ho Shin, Mischa Machius, Diana R. Tomchick, Thomas C. Südhof, Josep Rizo

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


The neuronal protein synaptotagmin 1 functions as a Ca2+ sensor in exocytosis via two Ca2+ -binding C2 domains. The very similar synaptotagmin 4, which includes all the predicted Ca2+- binding residues in the C2B domain but not in the C2A domain, is also thought to function as a neuronal Ca2+ sensor. Here we show that, unexpectedly, both C2 domains of fly synaptotagmin 4 exhibit Ca2+-dependent phospholipid binding, whereas neither C 2 domain of rat synaptotagmin 4 binds Ca2+ or phospholipids efficiently. Crystallography reveals that changes in the orientations of critical Ca2+ ligands, and perhaps their flexibility, render the rat synaptotagmin 4 C2B domain unable to form full Ca2+-binding sites. These results indicate that synaptotagmin 4 is a Ca2+ sensor in the fly but not in the rat, that the C 2+-binding properties of C2 domains cannot be reliab y predicted from sequence analyses, and that proteins clearly identified as orthologs may nevertheless have markedly different functional properties.

Original languageEnglish (US)
Pages (from-to)844-849
Number of pages6
JournalNature Structural and Molecular Biology
Issue number9
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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