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 language | English |
|---|---|
| Pages (from-to) | 25375-25386 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 291 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - 2 Dec 2016 |
Keywords
- cyclic AMP (cAMP)
- malaria
- plasmodium
- protein kinase A (PKA)
- protein structure
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Disrupting the allosteric interaction between the Plasmodium falciparum cAMP-dependent kinase and its regulatory subunit
AU - Littler, Dene R.
AU - Bullen, Hayley E.
AU - Harvey, Katherine L.
AU - Beddoe, Travis
AU - Crabb, Brendan S.
AU - Rossjohn, Jamie
AU - Gilson, Paul R.
PY - 2016/12/2
Y1 - 2016/12/2
N2 - 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.
AB - 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.
KW - cyclic AMP (cAMP)
KW - malaria
KW - plasmodium
KW - protein kinase A (PKA)
KW - protein structure
UR - http://www.scopus.com/inward/record.url?scp=85000461335&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.750174
DO - 10.1074/jbc.M116.750174
M3 - Article
AN - SCOPUS:85000461335
VL - 291
SP - 25375
EP - 25386
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 1083-351X
IS - 49
ER -