page 35 by Li and Camacho shows that some chaperones take a proactive stance on Ca2+ levels by regulating an ER Ca2+ pump.
Calcium must be pumped into the ER from the cytoplasm to maintain high levels for Ca2+-needy chaperones. This function is performed in many cells by the SERCA 2b pump. The authors show that some chaperones, in addition to helping newly synthesized proteins fold correctly, also inform SERCA 2b of the ER Ca2+ status. And what they have to say can alter pump activity.
High Ca2+ levels lowered pump activity by promoting an interaction between SERCA 2b and the chaperone ERp57, which catalyzed disulfide bridge formation in the lumenal portion of SERCA 2b. But the SERCA–ERp57 interaction was lost at lower ER Ca2+ concentrations. This reduced the disulfide bridge and converted the pump into its most active form. The ER is naturally an oxidizing environment, suggesting that a reductase may act on SERCA 2b unless ERp57 gets in the way.
Another chaperone, calreticulin (CRT), was needed for the ERp57–SERCA 2b interaction. CRT binds to both ERp57 and SERCA 2b, and SERCA 2b mutants that did not bind to CRT were not inhibited by ERp57. Thus, it is possible that CRT may be the actual calcium sensor—bringing ERp57 to SERCA only when Ca2+ levels are high enough and removing ERp57 when Ca2+ levels are lowered so that the stores are rapidly refilled. ▪