A Structural Basis for S100 Protein Specificity Derived from Comparative Analysis of Apo and Ca²⁺-Calcyclin

ISSN： 0022-2836

Source： Journal of Molecular Biology, Vol.317, Iss.2, 2002-03, pp. : 279-290

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Abstract

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.