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    Detailed characterization of the cooperative mechanism of calcium(2+) binding and catalytic activation in the sarcoplasmic reticulum calcium(2+) transport (SERCA) ATPase

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    Author
    Zhang, Zhongsen
    Advisor
    Inesi, Giuseppe
    Date
    2001
    Type
    dissertation
    
    Metadata
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    Abstract
    Occupation of two calcium-binding sites is required for catalytic activation of the sarcoplasmic reticulum Ca2+ ATPase (SERCA). The residues in the transmembrane domain, the cytoplasmic phosphorylation domain, and the L67 and L89 loops were subjected to mutational analysis. Direct measurements of Ca2+ binding and measurements of various enzymatic functions clarified the cooperative mechanism of calcium binding and catalytic activation of SERCA. The functional characterization and high-resolution structure of ATPase suggested cooperative and sequential calcium binding in which side chains of Glu771, Thr799, Asp800 and Glu908 contribute to site I, while Glu309, Asn796 and Asp800 contribute to site II. Mutational analysis of the L67 loop indicated its importance in protein folding and stabilization of the Ca 2+ ATPase. Single mutation of Pro820 to Ala resulted in negligible protein recovery while transcription occurred at normal levels. Single mutations of Lys819 or Arg822 interfered significantly with the formation of the phosphoenzyme intermediates. A triple conservative mutation of Asp813, 815 and 818 to Asn interfered mainly with the Ca2+-dependent activation of the ATPase but not Ca2+-independent phosphorylation by Pi. The effect of the triple mutation could be reproduced by a single mutation of Asp813 (but not of Asp815 or Asp818) to Asn. Functional and structural analysis of the experimental data demonstrates that the L67 loop plays an important role in protein folding and stabilization by linking the cytosolic catalytic domain and the transmembrane Ca2+ binding domain through a network of hydrogen bonds.
    Description
    University of Maryland, Baltimore. Biochemistry and Molecular Biology. Ph.D. 2001
    Keyword
    Biology, Molecular
    L67 loop
    transmembrane Ca2+ binding domain
    Catalytic Domain
    Sarcoplasmic Reticulum Calcium-Transporting ATPases
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1132
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