Molecular and functional dissection of the AP2-I/BDP1 transcriptional complex of the malaria parasite reveals a role beyond the red blood cell stages

The transcription factor AP2-I and the bromodomain protein BDP1 of the malaria parasite bind upstream of several genes implicated in red blood cell invasion. Here, we demonstrate that they form a complex and that AP2-I recruits BDP1 to the target genes. The ACDC domain of AP2-I interacts with a BDP1 region called BAAS, located between the ankyrin and the bromodomain. The ankyrin, in turn, binds to a conserved AP2-I specific region called ASAIR. Three of the interacting domains are parasite-specific, allowing inhibition without affecting the host. We further show that AP2-I is essential for asexual blood stage development, playing multiple roles, and that AP2-I and BDP1 function beyond invasion, binding to the promoters of the gametocytogenesis regulators gdv1 and ap2-g , suggesting a role for the AP2-I/BDP1 complex in parasite sexual commitment. Overall, our study highlights the essential and unique nature of the AP2-I/BDP1 complex and its potential as a novel antimalarial drug target.