Proton paths in the sarcoplasmic reticulum Ca-ATPase

The sarcoplasmic reticulum Ca²⁺-ATPase (SERCA1a) pumps Ca²⁺ and countertransport protons. Proton pathways in the Ca²⁺ bound and Ca²⁺-free states are suggested based on an analysis of crystal structures to which water molecules were added. The pathways are indicated by chains of water molecules that interact favorably with the protein. In the Ca²⁺ bound state Ca₂E1, one of the proposed Ca²⁺ entry paths is suggested to operate additionally or alternatively as proton pathway. In analogs of the ADP-insensitive phosphoenzyme E2P and in the Ca²⁺-free state E2, the proton path leads between transmembrane helices M5 to M8 from the lumenal side of the protein to the Ca²⁺ binding residues Glu-771, Asp-800 and Glu-908. The proton path is different from suggested Ca²⁺ dissociation pathways. We suggest that separate proton and Ca²⁺ pathways enable rapid (partial) neutralization of the empty cation binding sites. For this reason, transient protonation of empty cation binding sites and separate pathways for different ions are advantageous for P-type ATPases in general.