title: Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity.
abstract: PTPA, an essential and specific activator of protein phosphatase 2A (PP2A), functions as a peptidyl prolyl isomerase (PPIase). We present here the crystal structures of human PTPA and of the two yeast orthologs (Ypa1 and Ypa2), revealing an all alpha-helical protein fold that is radically different from other PPIases. The protein is organized into two domains separated by a groove lined by highly conserved residues. To understand the molecular mechanism of PTPA activity, Ypa1 was cocrystallized with a proline-containing PPIase peptide substrate. In the complex, the peptide binds at the interface of a peptide-induced dimer interface. Conserved residues of the interdomain groove contribute to the peptide binding site and dimer interface. Structure-guided mutational studies showed that in vivo PTPA activity is influenced by mutations on the surface of the peptide binding pocket, the same mutations that also influenced the in vitro activation of PP2Ai and PPIase activity.
authors.affiliation: Institut de Biochimie et de Biophysique Moléculaire et Cellulaire, UMR8619, Bât 430, Université de Paris-Sud, 91405 Orsay Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leulliot
authors.forename: Giorgia
authors.initials: G
authors.lastname: Vicentini
authors.forename: Jan
authors.initials: J
authors.lastname: Jordens
authors.forename: Sophie
authors.initials: S
authors.lastname: Quevillon-Cheruel
authors.forename: Marc
authors.initials: M
authors.lastname: Schiltz
authors.forename: David
authors.initials: D
authors.lastname: Barford
authors.forename: Herman
authors.initials: H
authors.lastname: van Tilbeurgh
authors.forename: Jozef
authors.initials: J
authors.lastname: Goris
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000737:chemistry; D019696:Peptidylprolyl Isomerase / Q000737:chemistry*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry*; D011392:Proline / Q000737:chemistry; D011487:Protein Conformation; D054648:Protein Phosphatase 2; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010455:Peptides; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases; D011392:Proline; D054648:Protein Phosphatase 2; D011506:Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C087440:PTPA protein, human; C490203:RRD1 protein, S cerevisiae; C502933:RRD2 protein, S cerevisiae