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Papers In Press, published online ahead of print December 20, 2001
Department of Cell Metabolism, National Institute of Haematology and Immunology, Budapest H-1113
Corresponding Author: enyedi{at}biomembrane.hu
The plasma membrane Ca2+ pump (PMCA) is an essential element in the complex of mechanisms which maintain low intracellular Ca2+ concentration in the living cell. This pump is tightly regulated by calmodulin through binding to a high affinity calmodulin-binding domain at the carboxyl terminus that also serves as an autoinhibitor of the enzyme. Inspection of the carboxyl terminus of hPMCA4b - the most widely distributed form of PMCA - revealed a caspase-3 consensus sequence (1077DEID1080) just a few residues upstream of the calmodulin-binding domain. We demonstrate here that in the early phase of apoptosis hPMCA4b is cleaved at aspartic acid D1080 in hPMCA4b transfected COS-7 cells or in HeLa cells which naturally express this protein. This cleavage of hPMCA4b produces a single 120 kDa fragment which is fully active in the absence of calmodulin, as the whole inhibitory region downstream of the 1077DEID1080 sequence is removed. Our experiments show that caspase-3 or a caspase-3-like protease is responsible for the formation of the constitutively active 120 kDa PMCA4b fragment: 1. Pretreatment of the cells with the caspase-3 inhibitor Z-DEVD-FMK was able to block the production of the 120 kDa fragment. 2. In vitro treatment of hPMCA4b with recombinant caspase-3 also generated a 120 kDa cleavage product, consistent with that seen in cells undergoing apoptosis. 3. Mutants in which the caspase-3 consensus sequence was altered (1077AEID1080, 1077DEIA1080 and 1077AEIA1080 mutants) were resistant to proteolysis. Based on these data, we conclude that hPMCA4b is a newly identified, natural caspase-3 substrate. We suggest that a constitutively active form of this protein, responding much faster to an increase in Ca2+concentration than the autoinhibited form, may have an important role in regulating intracellular Ca2+concentration in the apoptotic cell.
J. Biol. Chem, 10.1074/jbc.M109548200
Submitted on October 3, 2001
Revised on December 20, 2001
Accepted on December 20, 2001
Plasma membrane Ca2+ATPase isoform 4b is cleaved and activated by caspase-3 during the early phase of apoptosis
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