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

Abstract

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. Author summaryThe transcription factor AP2-I and the bromodomain protein BDP1 of the malaria parasite have previously been shown to be implicated in red blood cell invasion by the human malaria parasite. Here we show that they form a complex and identify the interacting domains on each protein. Three of these are parasite-specific, allowing inhibition without affecting the human host. We also show that AP2-I is essential for parasite survival in the blood and that the protein is implicated in other processes beyond red blood cell invasion. Namely, AP2-I, but also BDP1, bind to the promoters of the gametocytogenesis regulators gdv1 and ap2-g, suggesting a role for the AP2-I/BDP1 complex in parasite sexual commitment, without which the parasite cannot be transmitted.