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J. Biol. Chem., Vol. 277, Issue 9, 6822-6829, March 1, 2002
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From the The plasma membrane Ca2+ pump
(PMCA) is an essential element in the complex of mechanisms that
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 C terminus that also
serves as an autoinhibitor of the enzyme. Inspection of the C 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 Asp1080 in
hPMCA4b-transfected COS-7 cells or in HeLa cells that naturally express
this protein. This cleavage of hPMCA4b produces a single 120-kDa
fragment that is fully active in the absence of calmodulin, because 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
(benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone) 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.
Plasma Membrane Ca2+ATPase Isoform 4b Is Cleaved and
Activated by Caspase-3 during the Early Phase of Apoptosis*
,,¶
National Institute of Haematology and
Immunology, Daroczi ut 24, Budapest 1113, Hungary and the
§ Department of Biochemistry and Molecular Biology, Mayo
Foundation, Rochester, Minnesota 55905
*
This work was supported by Hungarian Academy of Sciences
Grants OTKA T034536, OTKA M36200, and OM Mu-00350/2000 (to A. E.), by
OTKA Postdoctoral Fellowship D38465 and Bolyai Janos Research Fellowship BO/00245/01 (to K. P.), and by National Institutes of
Health Grant GM28835 (to J. T. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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