A multipass membrane protein interacts with the cGMP-dependent protein kinase to regulate critical calcium signals in malaria parasites

ABSTRACT: In malaria parasites, all cGMP-dependent signalling is mediated through a single cGMP-dependent protein kinase (PKG). A major function of PKG is to control calcium signals essential for the parasite to exit red blood cells or for transmission to the mosquito vector. However, how PKG controls these signals in the absence of known second messenger-dependent calcium channels or scaffolding proteins remains a mystery. Here we identify a tightly-associated PKG partner protein in both Plasmodium falciparum asexual blood stages and P. berghei gametocytes. Named ICM1, the partner is a polytopic membrane protein with homology to transporters and calcium channels, raising the possibility of a direct functional link between PKG and calcium homeostasis. Phosphoproteomic analyses in both Plasmodium species highlight a densely phosphorylated region of ICM1 with multiple phosphorylation events dependent upon PKG activity. Stage-specific depletion of ICM1 in P. berghei blocks gametogenesis due to the inability of mutant parasites to mobilise intracellular calcium upon PKG activation, whilst conditional disruption of P. falciparum ICM1 results in reduced cGMP-dependent calcium mobilisation associated with defective egress and invasion. Our findings provide new insights into the atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Plasmodium Falciparum (isolate 3d7)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Helen Flynn  

LAB HEAD: Bram Snijders

PROVIDER: PXD020381 | Pride | 2021-02-10

REPOSITORIES: Pride