Centre of Microbial and

agr.kuleuven.ac.be EF-hand proteins are ubiquitous in eukaryotes and fulfil important regulatory or buffering roles. Calmodulin, a prototypical EF-hand protein, is a small (15–22 kDa), acidic (pI 3.9–4.3) Ca2+-binding protein that can interact with>25 distinct target proteins, thereby regulating the activity of many vital enzymes, including kinases, phosphatases, nitric oxide synthases, phosphodiesterases and ion channels [1]. Calmodulin is composed of four EF-hands organized in two pairs linked by a flexible central tether (Fig. 1a). The EF-hand motif was first discovered in the crystal structure of parvalbumin [2] and comprises two nearly perpendicular α-helices (named after helices E and F in parvalbumin) separated by a 12-residue loop [3]