A structural basis for S100 protein specificity derived from comparative analysis of apo and Ca2+-calcyclin

Calcyclin is a homodimeric protein belonging to the S100 subfamily of EF-hand Ca2+-binding proteins, which function in Ca2+ signal transduction processes. A refined high-resolution solution structure of Ca2+-bound rabbit calcyclin has been determined by heteronuclear solution NMR. In order to understand the Ca2+-induced structural changes in S100 proteins, in-depth comparative structural analyses were used to compare the apo and Ca2+-bound states of calcyclin, the closely related S100B, and the prototypical Ca2+-sensor protein calmodulin. Upon Ca2+ binding, the position and orientation of helix III in the second EF-hand is altered, whereas the rest of the protein, including the dimer interface, remains virtually unchanged. This Ca2+-induced structural change is much less drastic than the “opening” of the globular EF-hand domains that occurs in classical Ca2+ sensors, such as calmodulin. Using homology models of calcyclin based on S100B, a binding site in calcyclin has been proposed for the N-terminal domain of annexin XI and the C-terminal domain of the neuronal calcyclin-binding protein. The structural basis for the specificity of S100 proteins is discussed in terms of the variation in sequence of critical contact residues in the common S100 target-binding site.