A divergent cyclic nucleotide binding protein promotes Plasmodium ookinete infection of the mosquito
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Colonisation of the mosquito by the malarial parasite is critically reliant on the invasive ookinete stage. Ookinete invasion of mosquito is coordinated by the apical complex, a specialised parasite structure containing components for secretion, attachment and penetration. While studies have investigated cytoskeletal and secretory elements, it is currently unknown if signalling modules are present or functional at the apical complex. Here we elucidate the role of a cryptic cyclic nucleotide binding protein which we name CBP-O. PbCBP-O showed a marked localisation to the ookinete apex and disruption of the protein severely compromised ookinete invasion of mosquitos. Domain dissection analysis revealed that the N- and C-termini have distinct functions. Intriguingly, PbCBP-O exhibits dual binding specificity to both cGMP and cAMP. Our findings suggest the apical tip of the ookinete is a platform to transduce cyclic nucleotide signals essential for malaria parasite transmission.
Author summary
Malaria parasites complete their life-cycle within mammalian and mosquito hosts requiring specialised forms to invade and establish infection in host tissue. In order to transmit to the mosquito, the parasite forms a motile ookinete that uses the apical end to attach and penetrate the mosquito midgut membrane. Previous studies have identified several proteins localised to the apex of the ookinete. However, functions of many of these proteins are unknown. Here, we dissect the role of a putative cyclic nucleotide binding protein, CBP-O, in establishing ookinete infection within the mosquito. We discovered that in the absence of the protein, efficiency of transmission is significantly compromised. Interestingly the ability of ookinetes to move was not affected, but the parasites were unable to pass through the midgut membrane. We also reveal that both N- and C-terminal domains of the protein perform distinct functions and are both required for parasite transmission. Sequence and spatial conservation of the protein across the phylum Apicomplexa suggests an equivalent and crucial function of CBP-O in these parasites.
