Abstract
TvCyP1 and TvCyP2 are cyclophilin type peptidyl-prolyl isomerases present in the human parasite Trichomonas vaginalis. TvCyP1 interacts with the transcription factor Myb1 and assists in its nuclear translocation. Myb1 along with Myb2 and Myb3 regulates the expression of ap65-1 gene that encodes for a hydrogenosomal cytoadherence enzyme, thereby leading to pathogenesis. The crystal structures of TvCyP1 and its complex with the minimum TvCyP1-binding sequence of Myb1 (Myb1104-111) reported here shows that, TvCyP1 formed a homodimer as observed in solution. In the complex structure, P107 of one Myb1104-111 molecule was bound to the active site of each TvCyP1 protomer. NMR data further showed that TvCyP1 can catalyze the cis/trans isomerization of P107 in Myb1104-111. However, in the well-folded Myb1 protein (Myb135-141), P107 lies in a short loop surrounded by helices, making it difficult to bind to the active site of TvCyP1. NMR studies showed that similar to Myb1104-111 peptide, Myb135-141 also interacted with the active site of TvCyP1, facilitated by the slow dynamics in Myb135-141 surrounding P107. Identification of the two residues that are crucial in TvCyP1 dimerization led to the construction of a monomeric double mutant (FM-TvCyP1). Myb135-141 showed significantly weakened interaction with FM-TvCyP1, suggesting dimerization of TvCyP1 is essential for interaction with Myb135-141. This study provides detailed structural insights on TvCyP1-Myb1 interaction that could pave the way for newer drugs to treat drug-resistant strains.