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Original Article

Use of Penetrating Peptides Interacting with PP1/PP2A Proteins As a General Approach for a Drug Phosphatase Technology

Equipe Phosphatases, Unité de Chimie Organique (J.G., F.D., P.-E.B., A.G.), Logiciels et Banques de Données, Pôle Informatique (V.D.) and Unité d'Immunologie Moléculaire des Parasites, Unité de Recherche Associée 2581, Centre National de la Recherche Scientifique (S.B., O.M.-P.), Institut Pasteur, Paris, France; Laboratoire d'Immunologie Cellulaire et Tissulaire, Institut National de la Santé et de la Recherche Médicale U 543, Hôpital Pitié-Salpêtrière, Paris, France (A.R.); LEDAC Unité Mixte de Recherche Centre National de la Recherche Scientifique, Institut Albert Bonniot Faculté de Médecine, La Tronche, France (J.V.); Apoptose et Système Immunitaire, Institut Pasteur, Unité de Recherche Associée 1961, Centre National de la Recherche Scientifique, Paris, France (V.J.Y., S.A.S.); and Equipe Hypophyse, Unité Mixte de Recherche 6175, Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique-Université de Tours-Haras Nationaux, Physiologie de la Reproduction et des Comportements, Nouzilly, France (X.C.)

Abstract

Protein phosphatase types 1 (PP1) and 2A (PP2A) represent two major families of serine/threonine protein phosphatases that have been implicated in the regulation of many cellular processes, including cell growth and apoptosis in mammalian cells. PP1 and PP2A proteins are composed of oligomeric complexes comprising a catalytic structure (PP1c or PP2AC) containing the enzymatic activity and at least one more interacting subunit. The binding of different subunits to a catalytic structure generates a broad variety of holoenzymes. We showed here that casein kinase 2 (Ck2) and simian virus 40 small t antigen share a putative common -strand structure required for PP2A1 trimeric holoenzyme binding. We have also characterized DPT-sh1, a short basic peptide from Ck2 that interacted only in vitro with the PP2A-A subunit and behaves as a nontoxic penetrating shuttle in several cultivated human cell lines and chick embryos. In addition, DPT-sh1 specifically accumulated in human red cells infected with Plasmodium falciparum malaria parasites. We therefore designed bipartite peptides containing DPT-sh1 and PP1- or PP2A-interacting sequences. We found that DPT-5, a DPT-sh1-derived peptide containing a short sequence identified in CD28 antigen, interacts with PP2A-B, and DPT-7, another DPT-sh1-derived peptide containing a short sequence identified in Bad as a PP1 catalytic consensus docking motif, induce apoptosis in cultivated cell lines. These results clearly indicate that the rational design of PP1/PP2A interacting peptides is a pertinent strategy to deregulate intracellular survival pathways.

Address correspondence to: Alphonse Garcia, Equipe Phosphatases, Unité de Chimie Organique, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France. E-mail: agarcia{at}pasteur.fr

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