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Retinoic acid binds to the C2-domain of protein kinase Cα

AutorOchoa, Wendy F.; Torrecillas, Alejandro; Fita, Ignacio ; Verdaguer, Núria ; Corbalán-García, Senena; Gómez-Fernández, Juan C.
Fecha de publicación29-jul-2003
EditorAmerican Chemical Society
CitaciónBiochemistry 42(29): 8774- 877 (2003)
ResumenProtein kinase Cα (PKCα) is a key enzyme regulating the physiology of cells and their growth, differentiation, and apoptosis. PKC activity is known to be modulated by all-trans retinoic acid (atRA), although neither the action mechanism nor even the possible binding to PKCs has been established. Crystals of the C2-domain of PKCα, a regulatory module in the protein that binds Ca2+ and acidic phospholipids, have now been obtained by cocrystallization with atRA. The crystal structure, refined at 2.0 Å resolution, shows that RA binds to the C2-domain in two locations coincident with the two binding sites previously reported for acidic phospholipids. The first binding site corresponds to the Ca2+-binding pocket, where Ca2+ ions mediate the interactions of atRA with the protein, as they do with acidic phospholipids. The second binding site corresponds to the conserved lysine-rich cluster localized in β-strands three and four. These observations are strongly supported by [3H]-atRA-binding experiments combined with site-directed mutagenesis. Wild-type C2-domain binds 2 mol of atRA per mol of protein, while the rate reduces to one in the case of C2-domain variants, in which mutations affect either Ca2+ coordination or the integrity of the lysine-rich cluster site. Competition between atRA and acidic phospholipids to bind to PKC is a possible mechanism for modulating PKCα activity.
Versión del editorhttp://dx.doi.org/10.1021/bi034713g
Identificadoresdoi: 10.1021/bi034713g
issn: 0006-2960
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