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Research ArticleArticle

A Dynamic Model of Membrane-Bound Phospholipase Cβ2 Activation by Gβγ Subunits

Daniel S. Han, Urszula Golebiewska, Sebastian Stolzenberg, Suzanne F. Scarlata and Harel Weinstein
Molecular Pharmacology September 2011, 80 (3) 434-445; DOI: https://doi.org/10.1124/mol.111.073403
Daniel S. Han
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Urszula Golebiewska
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Sebastian Stolzenberg
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Suzanne F. Scarlata
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Harel Weinstein
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Abstract

Phospholipase C (PLC) β2, a well studied member of the family of enzymes that catalyze the hydrolysis of the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into secondary messengers, can be activated by the Gβγ subunits of heterotrimeric G-proteins in a manner that depends on the presence and composition of the associated phospholipid membrane surface. The N-terminal pleckstrin homology (PH) domain of PLCβ2 mediates both the response to Gβγ and membrane binding, but how these interactions are coupled to yield an activated catalytic core remains unknown. Here we propose a mechanism based on molecular models of truncated PLCβ2 in its activated form complexed with Gβγ and in the catalytically inactive/membrane-bound form, obtained with the application of protein-protein docking algorithms and coarse-grained molecular dynamics simulations. These models were probed experimentally, and the inferences were confirmed by results from a combination of molecular biology and fluorescence assays. Results from the dynamic simulations of the molecular models and their interactions with various lipid bilayers identify the determinants of PLCβ2-PH domain specificity for Gβγ and lipid membranes and suggest a mechanism for the previously reported dependence of Gβγ activation on the associated membrane composition. Together, these findings explain the roles of the different activators in terms of their effect on the orientations of the PH and catalytic core domains relative to the lipid membranes.

Footnotes

  • This work was supported by the National Institutes of Health National Institutes on Drug Abuse [Grants P01-DA012408, P01-DA012923, T32-DA007274]; and the National Institutes of Health National Institutes of General Medical Sciences [Grant R01-GM053132].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073403.

  • ABBREVIATIONS:

    PLC
    mammalian inositol-specific phospholipase C
    PH
    pleckstrin homology
    CAT
    catalytic
    POPC
    1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
    POPE
    1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine
    PIP2
    phosphatidylinositol 4,5-bisphosphate
    PC
    phosphocholine
    RMSD
    root-mean-square deviation
    MD
    molecular dynamics
    SASArel
    relative solvent-accessible solvent areas
    PHβ2
    pleckstrin homology domain of PLCβ2
    PLCβ2 chimera
    PHβ2-PLCδ1 chimera
    CPM
    7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin
    AS
    anthryloxystearic acid
    FRET
    Förster resonance energy transfer
    NBD
    nitrobenzofurazanylamino dodecanoic acid
    DOPC
    dioleoyl phosphatidylcholine
    DOPE
    dioleoyl phosphatidylethanolamine;
    LUV
    large unilamellar vesicle
    DABCYL
    4,4-dimethylamino-azobenzene-4′-carboxylic acid
    IP3
    inositol trisphosphate.

  • Received May 6, 2011.
  • Accepted June 20, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

A Dynamic Model of Membrane-Bound Phospholipase Cβ2 Activation by Gβγ Subunits

Daniel S. Han, Urszula Golebiewska, Sebastian Stolzenberg, Suzanne F. Scarlata and Harel Weinstein
Molecular Pharmacology September 1, 2011, 80 (3) 434-445; DOI: https://doi.org/10.1124/mol.111.073403

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Research ArticleArticle

A Dynamic Model of Membrane-Bound Phospholipase Cβ2 Activation by Gβγ Subunits

Daniel S. Han, Urszula Golebiewska, Sebastian Stolzenberg, Suzanne F. Scarlata and Harel Weinstein
Molecular Pharmacology September 1, 2011, 80 (3) 434-445; DOI: https://doi.org/10.1124/mol.111.073403
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