Calnuc is a novel, highly modular, EF‐hand containing, Ca2+‐binding, Golgi resident protein whose functions are not clear. Using amino acid sequences, we demonstrate that Calnuc is a highly conserved protein among various organisms, from Ciona intestinalis to humans. Maximum homology among all sequences is found in the region that binds to G‐proteins. In humans, it is known to be expressed in a variety of tissues, and it interacts with several important protein partners. Among other proteins, Calnuc is known to interact with heterotrimeric G‐proteins, specifically with the α‐subunit. Herein, we report the structural implications of Ca2+ and Mg2+ binding, and illustrate that Calnuc functions as a downstream effector for G‐protein α‐subunit. Our results show that Ca2+ binds with an affinity of 7 μm and causes structural changes. Although Mg2+ binds to Calnuc with very weak affinity, the structural changes that it causes are further enhanced by Ca2+ binding. Furthermore, isothermal titration calorimetry results show that Calnuc and the G‐protein bind with an affinity of 13 nm. We also predict a probable function for Calnuc, that of maintaining Ca2+ homeostasis in the cell. Using Stains‐all and terbium as Ca2+ mimic probes, we demonstrate that the Ca2+‐binding ability of Calnuc is governed by the activity‐based conformational state of the G‐protein. We propose that Calnuc adopts structural sites similar to the ones seen in proteins such as annexins, c2 domains or chromogrannin A, and therefore binds more calcium ions upon binding to Giα. With the number of organelle‐targeted G‐protein‐coupled receptors increasing, intracellular communication mediated by G‐proteins could become a new paradigm. In this regard, we propose that Calnuc could be involved in the downstream signaling of G‐proteins.

SummaryCalnuc is a recently discovered multidomain protein with EF-hand calcium binding sites. Several studies have reported various interacting partners for calnuc and, therefore, also different sites of localization in the cell. It interacts with important molecules such as DNA, G protein, COX, and amyloid precursor protein among others in addition to being involved in stress response and trafficking. The immense possibilities (of various functions this protein might be involved in) implicate great future in medicine and physiology. Preliminary studies also implicate the possibility of calnuc being involved in some of the human diseases. These initial observations imply the functions that this protein might be involved in. This review emphasizes the importance of further research on this protein. IUBMBIUBMB Life, 62(6): [436][437][438][439][440][441][442][443][444][445][446] 2010