Calmodulin, a regulatory partner of the estrogen receptor alpha in breast cancer cells

Although calmodulin (CaM) interaction with estrogen receptor alpha (ERα) has been known for more than two decades, it is only recently that the molecular mechanism of CaM-mediated regulation of ERα is beginning to emerge. Others and we have identified a putative calmodulin binding site (P295LMIKRSKKNSLALSTADQMVS317) in ERα, at the boundary between the hinge and the ligand binding domain. ERα mutations affecting its association with CaM have been reported to generate high basal, estrogen-independent transactivation activity, indicating that the P295–T317 sequence has an inhibitory function. Moreover, we found that a synthetic peptide (ERα17p: P295–T311) containing residues crucial for CaM binding exerts estrogenic effects on breast carcinoma cells. Finally, computer-aided conformational studies revealed that the CaM binding site might associate with a region located downstream in ERα (the β turn/H4 region), this association likely resulting in an auto-inhibitory folding of the receptor. Thus, we propose as a hypothesis that CaM acts as a positive regulator by relieving this ERα auto-inhibition.