Factors allowing small monovalent Li + to displace Ca 2+ in proteins.

Because Li + and Ca 2+ differ in both charge and size, the possibility that monovalent Li + could dislodge the bulkier, divalent Ca 2+ in Ca 2+ proteins had not been considered. However, our recent density functional theory/continuum dielectric calculations predicted that Li + could displace the native Ca 2+ from the C2 domain of cytosolic PKCα/γ. This would reduce electrostatic interactions between the Li + -bound C2 domain and the membrane, consistent with experimental studies showing that Li + can inhibit the translocation of cytoplasmic PKC to membranes. Besides the trinuclear Ca 2+ -site in the PKCα/γ C2 domain, it is not known whether other Ca 2+ -sites in human proteins may be susceptible to Li + substitution. Furthermore, it is unclear what factors determine the outcome of the competition between divalent Ca 2+ and monovalent Li + . Here we show that the net charge of residues in the first and second coordination shell is a key determinant of the selectivity for divalent Ca 2+ over monovalent Li + in proteins: neutral/anionic Ca 2+ -carboxylate sites are protected against Li + attack. They are further protected by outer-shell Asp - /Glu - and the protein matrix rigidifying the Ca 2+ -site or limiting water entry. In contrast, buried, cationic Ca 2+ -sites surrounded by Arg + /Lys + , which are found in the C2 domains of PKCα/γ, as well as certain synaptotagmins, are prone to Li + attack.