Liquid-liquid phase separation (LLPS) as a sensing and adaptation mechanism: An evidence-based hypothesis on AP2 transcription factors in the malaria parasite

BackgroundProtein liquid-liquid phase separation (LLPS) can be driven by prion-like domains (PrLDs) inside intrinsically disordered regions (IDRs). The causing agent of the deadliest form of human malaria, Plasmodium falciparum, has abundant prion-like proteins whose aggregation is presumed to have a functional role. Multiple members of the largest family of transcription factors in P. falciparum, AP2 (PfAP2), responsible for adapting the parasite gene response in different scenarios, were found in aggregation-prone protein screenings. ResultsWe show that the PfAP2s members carry the physicochemical determinants to perform LLPS forming biomolecular condensates in vivo. The long IDRs of PfAP2s could sense changes in the cellular microenvironment, and their PrLDs could drive conformational rearrangements. PfAP2s do not function as centralizing hubs for protein-protein interaction networks, but display significant preferred interactions among themselves, establishing a large, connected subnetwork. Predictions suggest that all PfAP2s have regions to localize into LLPS-condensates, while larger PfAP2s could initiate condensation. We show that four PfAP2 members co-localize in live P. falciparum, bearing the potential to be engaged in LLPS-condensates. ConclusionWe present bioinformatics analyses and experimental data obtained in live parasites suggesting that PfAP2s are able to direct LLPS in P. falciparum. We propose a model in which sensing by the parasite of cellular stresses like host transfer, temperature changes and energy depletion, and the corresponding gene responses are driven by LLPS where the PfAP2 family plays a fundamental role. Finally, we postulate targeting PfAP2 as a new therapeutic antimalarial strategy to curb the emergence of drug-resistant parasites.