Role of electrostatic and hydrophobic interactions in Ca2+-dependent phospholipid binding by the C2A-domain from synaptotagmin I

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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Most C2-domains bind to phospholipid bilayers as a function of Ca2+. Although phospholipid binding is central for the normal functions of C2-domain proteins, the precise mechanism of phospholipid binding is unclear. One of the key questions is whether phospholipid binding by C2-domains is primarily governed by electrostatic or hydrophobic interactions. We have now examined this question for the C2A-domain of synaptotagmin I, a membrane protein of secretory vesicles with an essential function in Ca2+-triggered exocytosis. Our results confirm previous data showing that Ca2+-dependent phospholipid binding by the synaptotagmin C2A-domain is exquisitely sensitive to ionic strength, suggesting an essential role for electrostatic interactions. However, we find that hydrophobic interactions mediated by exposed residues in the Ca2+-binding loops of the C2A-domain, in particular methionine 173, are also essential for tight phospholipid binding. Furthermore, we demonstrate that the apparent Ca2+ affinity of the C2A-domain is determined not only by electrostatic interactions as shown previously, but also by hydrophobic interactions. Together these data indicate that phospholipid binding by the C2A-domain, although triggered by an electrostatic Ca2+-dependent switch, is stabilized by a hydrophobic mechanism. As a result, Ca2+-dependent phospholipid binding proceeds by a multimodal mechanism that mirrors the amphipathic nature of the phospholipid bilayer. The complex phospholipid binding mode of synaptotagmins may be important for its role in regulated exocytosis of secretory granules and synaptic vesicles.

Original languageEnglish (US)
Pages (from-to)S12-S18
Issue numberSUPPL.
StatePublished - 2002

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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