Nature Structural & Molecular Biology
11, 844 - 849 (2004)
Published online: 15 August 2004; | doi:10.1038/nsmb817
Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4Han Dai1, 2, Ok-Ho Shin3, 4, 5, Mischa Machius1, Diana R Tomchick1, Thomas C Südhof3, 4, 5
& Josep Rizo1, 21
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 2
Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 3
Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 4
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 5
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Correspondence should be addressed to Josep Rizo jose@arnie.swmed.eduThe 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 C2 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 Ca2+-binding properties of C2 domains cannot be reliably predicted from sequence analyses, and that proteins clearly identified as orthologs may nevertheless have markedly different functional properties.
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