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Originally published In Press as doi:10.1074/jbc.M205457200 on July 26, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36146-36151, September 27, 2002
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Asp1080 Upstream of the Calmodulin-binding Domain Is Critical for Autoinhibition of hPMCA4b*

Katalin PásztyDagger , Alan R. Penheiter§, Anil K. Verma§, Rita Padányi, Adelaida G. Filoteo§, John T. Penniston§, and Ágnes Enyedi||

From the  National Medical Center, Institute of Haematology and Immunology, Diószegi u. 64, H-1113 Budapest, Hungary, Dagger  Membrane Research Group of the Hungarian Academy of Sciences, Nador u. 7, H-1051, Budapest, Hungary, and § Department of Biochemistry and Molecular Biology, Mayo Foundation, Rochester, Minnesota 55905

The role of the plasma membrane Ca2+ pump (PMCA) is to remove excess Ca2+ from the cytosol to maintain low intracellular Ca2+ levels. Asp1080 lies within an acidic sequence between the C-terminal inhibitory region and the catalytic core of PMCAs and is part of the caspase-3 recognition site of isoform 4b. Caspase-3 cuts immediately after this residue and activates the pump by removing the inhibitory region (Pászty, K., Verma, A. K., Padányi, R., Filoteo, A. G., Penniston, J. T., and Enyedi, Á. (2002) J. Biol. Chem. 277, 6822-6829). Asp1080 had not been believed to have any other role, but here we show that it also plays a critical role in the autoinhibition and calmodulin activation of PMCA4b. Site-specific mutation of Asp1080 to Asn, Ala, or Lys in PMCA4b resulted in a substantial increase in the basal activity in the absence of calmodulin. All Asp1080 mutants exhibited an increased affinity for calmodulin because of an increase in the rate of activation by calmodulin. This rate was higher when the inhibition was weaker, showing that a strong inhibitory interaction slows the activation rate. In contrast, mutating the nearby Asp1077 had no effect on basal activity or calmodulin activation. We propose that the conserved Asp1080, even though it is neither in the regulatory domain nor in the catalytic core, plays an essential role in inhibition by stabilizing the inhibited state of the enzyme.

* This work was supported in part by Hungarian Academy of Sciences Grants OTKA T034536, OTKA M36200, OM Mu-00350/2000, and ETT 205/2001 (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.

|| To whom correspondence should be addressed. Tel.: 36-1-372-4353; Fax: 36-1-372-4353; E-mail: enyedi@biomembrane.hu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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