Common EF-hand motifs in cholinesterases and neuroligins suggest a role for Ca2+ binding in cell surface associations

Comparisons of protein sequence via cyclic training of Hidden Markov Models (HMMs) in conjunction with alignments of three-dimensional structure, usin g the Combinatorial Extension (CE) algorithm, reveal two putative EF-hand m etal binding domains in acetylcholinesterase. Based on sequence similarity, putative EF-hands are also predicted for the neuroligin family of cell sur face proteins. These predictions are supported by experimental evidence. In the acetylcholinesterase crystal structure from Torpedo californica, the f irst putative EF-hand region binds the Zn2+ found in the heavy metal replac ement structure. Further, the interaction of neuroligin 1 with its cognate receptor neurexin depends on Ca2+. Thus, members of the alpha,beta hydrolas e fold family of proteins contain potential Ca2+ binding sites, which in so me family members may be critical for heterologous cell associations.