No abstract

Calcium carries messages to virtually all important functions of cells. Although it was already active in unicellular organisms, its role became universally important after the transition to multicellular life. In this Minireview, we explore how calcium ended up in this privileged position. Most likely its unique coordination chemistry was a decisive factor as it makes its binding by complex molecules particularly easy even in the presence of large excesses of other cations, e.g. magnesium. Its free concentration within cells can thus be maintained at the very low levels demanded by the signaling function. A large cadre of proteins has evolved to bind or transport calcium. They all contribute to buffer it within cells, but a number of them also decode its message for the benefit of the target. The most important of these "calcium sensors" are the EF-hand proteins. Calcium is an ambivalent messenger. Although essential to the correct functioning of cell processes, if not carefully controlled spatially and temporally within cells, it generates variously severe cell dysfunctions, and even cell death.At the beginning, life on earth consisted of single cells that were capable of carrying out all vital functions. The interplay with other cells was largely limited to the competition for nutrients. Unicellularity was clearly successful, as shown by the fact that unicellular organisms are actually still predominant today. Nevertheless, at a time which was generally estimated to be at 600 -700 million years ago, but which is now being pushed back to more than 2 billion years ago (1, 2), competition was replaced by cooperation, and multicellular life evolved. It had somehow become advantageous for cells to work together rather than to live alone. Cells became gradually organized into structures in which they learned to perform different tasks and to cooperate in the division of labor. Cooperation naturally demanded the communication of cells with each other, i.e. it demanded the development of agents that could exchange messages between cells. As the complexity of the multicellular organization increased, so did the number of cells with distinct functional tasks. The number of intercellular signaling molecules and the degree of their complexity increased in parallel. A basic tenet of life is regulation. Thus, all vital functions within the cells are regulated. Indeed, they are also regulated in unicellular organisms. However, the transition to multicellular life brought with it the intercellular exchange of messages as an additional, and essential, regulation category.Calcium, the third most abundant metal in nature, was amply available to cells from the beginning, and was adopted as a regulator at an early evolutionary stage. The basic principles of calcium regulation were already present in prokaryotes and protists (3, 4), but calcium regulation gradually grew to cover nearly all aspects of cell function after the transition to multicellularity. Naturally, agents that carry messages to intracellular targets must be maint...

The three-dimensional structure of the complex between calmodulin (CaM) and a peptide corresponding to the N-terminal portion of the CaM-binding domain of the plasma membrane calcium pump, the peptide C20W, has been solved by heteronuclear three-dimensional nuclear magnetic resonance (NMR) spectroscopy. The structure calculation is based on a total of 1808 intramolecular NOEs and 49 intermolecular NOEs between the peptide C20W and calmodulin from heteronuclear-filtered NOESY spectra and a half-filtered experiment, respectively. Chemical shift differences between free Ca(2+)-saturated CaM and its complex with C20W as well as the structure calculation reveal that C20W binds solely to the C-terminal half of CaM. In addition, comparison of the methyl resonances of the nine assigned methionine residues of free Ca(2+)-saturated CaM with those of the CaM/C20W complex revealed a significant difference between the N-terminal and the C-terminal domain; i.e., resonances in the N-terminal domain of the complex were much more similar to those reported for free CaM in contrast to those in the C-terminal half which were significantly different not only from the resonances of free CaM but also from those reported for the CaM/M13 complex. As a consequence, the global structure of the CaM/C20W complex is unusual, i.e., different from other peptide calmodulin complexes, since we find no indication for a collapsed structure. The fine modulation in the peptide protein interface shows a number of differences to the CaM/M13 complex studied by Ikura et al. [Ikura, M., Clore, G. M., Gronenborn, A. M., Zhu, G., Klee, C. B., and Bax, A. (1992) Science 256, 632-638]. The unusual binding mode to only the C-terminal half of CaM is in agreement with the biochemical observation that the calcium pump can be activated by the C-terminal half of CaM alone [Guerini, D., Krebs, J., and Carafoli, E. (1984) J. Biol. Chem. 259, 15172-15177].