Factors allowing small monovalent Li+ to displace Ca2+ in proteins

Abstract

Because Li⁺ and Ca²⁺ differ in both charge and size, the possibility that monovalent Li⁺ could dislodge the bulkier, divalent Ca²⁺ in Ca²⁺ proteins had not been considered. However, our recent density functional theory/continuum dielectric calculations predicted that Li⁺ could displace the native Ca²⁺ 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 Ca²⁺-site in the PKCα/γ C2 domain, it is not known whether other Ca²⁺-sites in human proteins may be susceptible to Li⁺ substitution. Furthermore, it is unclear what factors determine the outcome of the competition between divalent Ca²⁺ 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 Ca²⁺ over monovalent Li⁺ in proteins: neutral/anionic Ca²⁺-carboxylate sites are protected against Li⁺ attack. They are further protected by outer-shell Asp⁻/Glu⁻ and the protein matrix rigidifying the Ca²⁺-site or limiting water entry. In contrast, buried, cationic Ca²⁺-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.