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 journalArticle

67 Citations (Scopus)

Abstract

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
Volume11
Issue number9
DOIs
StatePublished - Sep 2004
Externally publishedYes

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Synaptotagmins
Diptera
Phospholipids
Synaptotagmin I
Crystallography
Protein Sequence Analysis
Exocytosis
Binding Sites
Ligands
C2 Domains
Proteins

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Dai, H., Shin, O. H., Machius, M., Tomchick, D. R., Südhof, T. C., & Rizo, J. (2004). Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. Nature Structural and Molecular Biology, 11(9), 844-849. https://doi.org/10.1038/nsmb817

Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. / Dai, Han; Shin, Ok Ho; Machius, Mischa; Tomchick, Diana R.; Südhof, Thomas C.; Rizo, Josep.

In: Nature Structural and Molecular Biology, Vol. 11, No. 9, 09.2004, p. 844-849.

Research output: Contribution to journalArticle

Dai, H, Shin, OH, Machius, M, Tomchick, DR, Südhof, TC & Rizo, J 2004, 'Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4', Nature Structural and Molecular Biology, vol. 11, no. 9, pp. 844-849. https://doi.org/10.1038/nsmb817
Dai, Han ; Shin, Ok Ho ; Machius, Mischa ; Tomchick, Diana R. ; Südhof, Thomas C. ; Rizo, Josep. / Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. In: Nature Structural and Molecular Biology. 2004 ; Vol. 11, No. 9. pp. 844-849.
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