Disrupting the allosteric interaction between the Plasmodium falciparum cAMP-dependent kinase and its regulatory subunit

Dene R. Littler, Hayley E. Bullen, Katherine L. Harvey, Travis Beddoe, Brendan S. Crabb, Jamie Rossjohn, Paul R. Gilson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The ubiquitous second messenger cAMP mediates signal transduction processes in the malarial parasite that regulate host erythrocyte invasion and the proliferation of merozoites. In Plasmodium falciparum, the central receptor for cAMP is the single regulatory subunit (R) of protein kinase A (PKA). To aid the development of compounds that can selectively dysregulate parasite PKA signaling, we solved the structure of the PKA regulatory subunit in complex with cAMP and a related analogue that displays antimalarial activity, (Sp)-2-Cl-cAMPS. Prior to signaling, PKA-R holds the kinase's catalytic subunit (C) in an inactive state by exerting an allosteric inhibitory effect. When two cAMP molecules bind to PKA-R, they stabilize a structural conformation that facilitates its dissociation, freeing PKA-C to phosphorylate downstream substrates such as apical membrane antigen 1. Although PKA activity was known to be necessary for erythrocytic proliferation, we show that uncontrolled induction of PKA activity using membrane-permeable agonists is equally disruptive to growth.

Original languageEnglish
Pages (from-to)25375-25386
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number49
DOIs
Publication statusPublished - 2 Dec 2016

Keywords

  • cyclic AMP (cAMP)
  • malaria
  • plasmodium
  • protein kinase A (PKA)
  • protein structure

Cite this

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title = "Disrupting the allosteric interaction between the Plasmodium falciparum cAMP-dependent kinase and its regulatory subunit",
abstract = "The ubiquitous second messenger cAMP mediates signal transduction processes in the malarial parasite that regulate host erythrocyte invasion and the proliferation of merozoites. In Plasmodium falciparum, the central receptor for cAMP is the single regulatory subunit (R) of protein kinase A (PKA). To aid the development of compounds that can selectively dysregulate parasite PKA signaling, we solved the structure of the PKA regulatory subunit in complex with cAMP and a related analogue that displays antimalarial activity, (Sp)-2-Cl-cAMPS. Prior to signaling, PKA-R holds the kinase's catalytic subunit (C) in an inactive state by exerting an allosteric inhibitory effect. When two cAMP molecules bind to PKA-R, they stabilize a structural conformation that facilitates its dissociation, freeing PKA-C to phosphorylate downstream substrates such as apical membrane antigen 1. Although PKA activity was known to be necessary for erythrocytic proliferation, we show that uncontrolled induction of PKA activity using membrane-permeable agonists is equally disruptive to growth.",
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Disrupting the allosteric interaction between the Plasmodium falciparum cAMP-dependent kinase and its regulatory subunit. / Littler, Dene R.; Bullen, Hayley E.; Harvey, Katherine L.; Beddoe, Travis; Crabb, Brendan S.; Rossjohn, Jamie; Gilson, Paul R.

In: Journal of Biological Chemistry, Vol. 291, No. 49, 02.12.2016, p. 25375-25386.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gilson, Paul R.

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