Abstract
The Ca(2+)-sensing receptor (CaSR) is a member of family C of the GPCRs responsible for sensing extracellular Ca(2+) ([Ca(2+)](o)) levels, maintaining extracellular Ca(2+) homeostasis, and transducing Ca(2+) signaling from the extracellular milieu to the intracellular environment. In the present study, we have demonstrated a Ca(2+)-dependent, stoichiometric interaction between CaM and a CaM-binding domain (CaMBD) located within the C terminus of CaSR (residues 871-898). Our studies suggest a wrapping around 1-14-like mode of interaction that involves global conformational changes in both lobes of CaM with concomitant formation of a helical structure in the CaMBD. More importantly, the Ca(2+)-dependent association between CaM and the C terminus of CaSR is critical for maintaining proper responsiveness of intracellular Ca(2+) responses to changes in extracellular Ca(2+) and regulating cell surface expression of the receptor.
Highlights
A CaM-binding site in the C-terminal region of Ca2؉-sensing receptor (CaSR) was predicted by the calmodulin target data base (17)
Helical wheel analysis of the predicted CaM-binding region in CaSR shows that most of the positively charged residues segregate on one side, whereas the hydrophobic residues are located on the other, which is similar to the CaM-binding regions in other proteins, such as myosin light chain kinases
We have characterized how CaM interacts with the C-tail of CaSR, a member of the family C G protein-coupled receptors (GPCR) responsible for sensing extracellular Ca2ϩ levels, maintaining extracellular Ca2ϩ homeostasis, and transducing cal
Summary
The 216-residue C-tail has been reported to interact with a number of proteins, including filamin-A (7), potassium channels (8), and E3 ubiquitin ligase (9). Previous studies have shown that truncations at the C terminus of CaSR can cause either loss- or gain-of-function of the receptor. Truncation at residues 874 (10) or 876 (11) results in loss of responsiveness to [Ca2ϩ]o, whereas truncation between 895 and 1075 causes overreactivity of CaSR toward [Ca2ϩ]o (12). Taken together, these findings strongly indicate that the sequence between 874 and 895 in the C terminus of CaSR is crucial for proper intracellular signaling cascades in response to external stimuli. We report for the first time the prediction of a CaM-
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