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Determinants for Substrate Specificity of Protein Phosphatase 2A.

ABSTRACT: Protein phosphatase 2A- (PP2A-) catalyzed dephosphorylation of target substrate proteins is widespread and critical for cellular function. PP2A is predominantly found as a heterotrimeric complex of a catalytic subunit (C), a scaffolding subunit (A), and one member of 4 families of regulatory subunits (B). Substrate specificity of the holoenzyme complex is determined by the subcellular locale the complex is confined to, selective incorporation of the B subunit, interactions with endogenous inhibitory proteins, and specific intermolecular interactions between PP2A and target substrates. Here, we discuss recent studies that have advanced our understanding of the molecular determinants for PP2A substrate specificity.

SUBMITTER: Slupe AM

PROVIDER: S-EPMC3132988 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Determinants for Substrate Specificity of Protein Phosphatase 2A.

Slupe Andrew M AM Merrill Ronald A RA Strack Stefan S

Enzyme research 20110702

Protein phosphatase 2A- (PP2A-) catalyzed dephosphorylation of target substrate proteins is widespread and critical for cellular function. PP2A is predominantly found as a heterotrimeric complex of a catalytic subunit (C), a scaffolding subunit (A), and one member of 4 families of regulatory subunits (B). Substrate specificity of the holoenzyme complex is determined by the subcellular locale the complex is confined to, selective incorporation of the B subunit, interactions with endogenous inhibi ...[more]

PMID: 21755039

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Project description:UnlabelledProtein phosphorylation has become increasingly recognized for its role in regulating bacterial physiology and virulence. Chlamydia spp. encode two validated Hanks'-type Ser/Thr protein kinases, which typically function with cognate protein phosphatases and appear capable of global protein phosphorylation. Consequently, we sought to identify a Ser/Thr protein phosphatase partner for the chlamydial kinases. CTL0511 from Chlamydia trachomatis L2 434/Bu, which has homologs in all sequenced Chlamydia spp., is a predicted type 2C Ser/Thr protein phosphatase (PP2C). Recombinant maltose-binding protein (MBP)-tagged CTL0511 (rCTL0511) hydrolyzed p-nitrophenyl phosphate (pNPP), a generic phosphatase substrate, in a MnCl2-dependent manner at physiological pH. Assays using phosphopeptide substrates revealed that rCTL0511 can dephosphorylate phosphorylated serine (P-Ser), P-Thr, and P-Tyr residues using either MnCl2 or MgCl2, indicating that metal usage can alter substrate preference. Phosphatase activity was unaffected by PP1, PP2A, and PP3 phosphatase inhibitors, while mutation of conserved PP2C residues significantly inhibited activity. Finally, phosphatase activity was detected in elementary body (EB) and reticulate body (RB) lysates, supporting a role for protein dephosphorylation in chlamydial development. These findings support that CTL0511 is a metal-dependent protein phosphatase with broad substrate specificity, substantiating a reversible phosphorylation network in C. trachomatisImportanceChlamydia spp. are obligate intracellular bacterial pathogens responsible for a variety of diseases in humans and economically important animal species. Our work demonstrates that Chlamydia spp. produce a PP2C capable of dephosphorylating P-Thr, P-Ser, and P-Tyr and that Chlamydia trachomatis EBs and RBs possess phosphatase activity. In conjunction with the chlamydial Hanks'-type kinases Pkn1 and PknD, validation of CTL0511 fulfills the enzymatic requirements for a reversible phosphoprotein network. As protein phosphorylation regulates important cellular processes, including metabolism, differentiation, and virulence, in other bacterial pathogens, these results set the stage for elucidating the role of global protein phosphorylation in chlamydial physiology and virulence.

Dataset Information

Determinants for Substrate Specificity of Protein Phosphatase 2A.

Publications

Determinants for Substrate Specificity of Protein Phosphatase 2A.

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