Structure of the protein kinase Cβ phospholipid-binding C2 domain complexed with Ca2+

R. Bryan Sutton, Stephen R. Sprang

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


Background: Conventional isoforms (α, β and γ) of protein kinase C (PKC) are synergistically activated by phosphatidylserine and Ca2+; both bind to C2 domains located within the PKC amino-terminal regulatory regions. C2 domains contain a bipartite or tripartite Ca2+-binding site formed by opposing loops at one end of the protein. Neither the structural basis for cooperativity between phosphatidylserine and Ca2+, nor the binding site for phosphatidylserine are known. Results: The structure of the C2 domain from PKCβ complexed with Ca2+ and o-phospho-L-serine has been determined to 2.7 Å resolution using X-ray crystallography. The eight-stranded, Greek key β-sandwich fold of PKCβ-C2 is similar to that of the synaptotagmin I type I C2 domain. Three Ca2+ ions, one at a novel site, were located, each sharing common aspartate ligands. One of these ligands is donated by a dyad-related C2 molecule. A phosphoserine molecule binds to a lysine-rich cluster in C2. Conclusions: Shared ligation among the three Ca2+ ions suggests that they bind cooperatively to PKCβ-C2. Cooperativity may be compromised by the accumulation of positive charge in the binding site as successive ions are bound. Model building shows that the C1 domain could provide carboxylate and carbonyl ligands for two of the three Ca2+ sites. Ca2+-mediated interactions between the two domains could contribute to enzyme activation as well as to the creation of a positively charged phosphatidylserine-binding site.

Original languageEnglish
Pages (from-to)1395-1405
Number of pages11
Issue number11
StatePublished - Nov 15 1998


  • Calcium
  • Protein conformation
  • Protein kinases
  • Protein structure
  • X-ray crystallography


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