Use of penetrating peptides interacting with PP1/PP2A proteins as a general approach for a drug phosphatase technology.
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 2alpha (Ck2alpha) and simian virus 40 small t antigen share a putative common beta-strand structure required for PP2A1 trimeric holoenzyme binding. We have also characterized DPT-sh1, a short basic peptide from Ck2alpha 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-Balpha, 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.
Guergnon
Julien
J
Equipe Phosphatases, Unité de Chimie Organique, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.
Dessauge
Frédéric
F
Dominguez
Victoria
V
Viallet
Jean
J
Bonnefoy
Serge
S
Yuste
Victor J
VJ
Mercereau-Puijalon
Odile
O
Cayla
Xavier
X
Rebollo
Angelita
A
Susin
Santos A
SA
Bost
Pierre-Etienne
PE
Garcia
Alphonse
A
D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism; D020134:Catalytic Domain; D002642:Chick Embryo; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017386:Sequence Homology, Amino Acid
D010455:Peptides; D047390:Casein Kinase II; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1