Membrane domain formation by calcium-dependent, lipid-binding proteins: Insights from the C2 motif

Anne K. Hinderliter, Paulo F.F. Almeida, Rodney L. Biltonen, Carl E. Creutz

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

We propose a novel role in cellular function for some membrane-binding proteins and, specifically, the C2 motif. The C2 motif binds phospholipid in a manner that is modulated by Ca2+ and is thought to confer membrane-binding ability on a wide variety of proteins, primarily proteins involved in signal transduction and membrane trafficking events. We hypothesize that in the absence of Ca2+ the C2 motif couples the free energy of binding to a bilayer membrane comprised of zwitterionic and negatively charged lipids to the formation of a domain enriched in the negative lipids. This in turn leads to the dynamic clustering of bound homologous or heterologous proteins incorporating the C2 motif, or other acidic lipid-binding motifs. In the presence of Ca2+, the protein clusters may be further stabilized. In support of this hypothesis we present evidence for membrane domain formation by the first C2 domain of synaptotagmin in the absence of Ca2+. Fluid state phospholipid mixtures incorporating a pyrene-labeled phospholipid probe exhibited a change in pyrene excimer/monomer fluorescence ratio consistent with domain formation upon binding the C2 domain. In addition, we present the results of simulations of the interaction of the C2 domain with the membrane that indicate that protein clusters and lipid domains form in concert. Copyright (C) 1998 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)227-235
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1448
Issue number2
DOIs
StatePublished - Dec 10 1998
Externally publishedYes

Bibliographical note

Funding Information:
We are indebted to Sandy Snyder, Cynthia Damer, and Jose Tomsig for advice and assistance in the preparation of the recombinant C2 domain. This study was supported by the NIH (GM53266, NS31618, and GM37658) and the NSF (MCB9632095).

Keywords

  • Annexin
  • C2 motif
  • Ca- and lipid-binding proteins
  • Membrane domain
  • Monte Carlo simulation
  • Pyrene fluorescence

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