Phosphorylation Dependent Assembly of a 14-3-3 Anchored Signaling Complex During Erythrocyte Invasion by Plasmodium falciparum Merozoites
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ABSTRACT: Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signalling pathways. However, the signalling pathways in merozoites that regulate microneme secretion and RBC invasion are not completely understood. Exposure of P. falciparum merozoites to a low potassium (K+) ionic environment as found in blood plasma has been shown to lead to a rise in cytosolic calcium (Ca2+), which triggers microneme secretion. Here, we present a phosphoproteome analysis of extracellular merozoites revealing 3700 phosphorylation sites of which 1705 were not previously known. Upon investigation of phosphorylation changes in merozoites subjected to different ionic environments (high K+/ low K+) we identified 394 protein phosphorylation sites out of which changes in 143 were Ca2+-dependent. We observed that the catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr), calcium-dependent protein kinase 1 (PfCDPK1) and scaffold protein Pf14-3-3I form a phosphorylation-dependent multiprotein complex when merozoites are exposed to the low K+ signal. Moreover, disruption of this complex using phospho-peptides, or small molecule inhibitors blocks microneme secretion and RBC invasion. This study sheds light on the regulatory mechanisms used by merozoites to invade RBCs and identifies new targets for development of drugs against malaria.
INSTRUMENT(S): LTQ Orbitrap Velos
ORGANISM(S): Plasmodium Falciparum (isolate 3d7)
DISEASE(S): Plasmodium Falciparum Malaria
SUBMITTER: Thibaut Douché
LAB HEAD: Chetan Chitnis
PROVIDER: PXD015093 | Pride | 2021-03-05
REPOSITORIES: Pride
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