The Whole Is Not the Simple Sum of Its Parts in Calmodulin fromS.cerevisiae†

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Abstract
Calmodulin is an essential Ca2+-binding protein involved in a multitude of cellular processes. The calmodulin sequence is highly conserved among all eukaryotic species; calmodulin from the yeast S.cerevisiae (yCaM) is the most divergent form, while still sharing 60% sequence identity with vertebrate calmodulin (vCaM). Although yCaM can be functionally substituted by vCaM in vivo, the two calmodulin proteins possess significantly different Ca2+-binding properties as well as abilities to activate vertebrate target enzymes in vitro. In addition, it has been observed that certain properties of the N-terminal and C-terminal domains of Ca2+-yCaM differ depending on whether they are in the context of the whole protein or isolated as half-molecule fragments. To investigate the structural basis for these differing properties, we have undertaken nuclear magnetic resonance (NMR) studies on yCaM and the two half-molecule fragments representing its two individual domains, yTr1(residues 1−76) and yTr2 (residues 75−146). We present direct evidence that the two domains of Ca2+-yCaM interact via their exposed hydrophobic surfaces. Thus, the Ca2+-bound form of yCaM exists in a novel compact structure in direct contrast to the well-established structure of Ca2+-vCaM comprised of two independent globular domains.