Abstract
In Trichomonas vaginalis (T. vaginalis), cyclophilins play a vital role in dislodging Myb proteins from the membrane compartment and leading them to nuclear translocation. We previously reported that TvCyP1 cyclophilin from T. vaginalis forms a dimer and plays an essential role in moving the Myb1 transcription factor toward the nucleus. In comparison, TvCyP2 containing an extended segment at the N-terminus (N-terminal segment) formed a monomer and showed a different role in regulating protein trafficking. Four X-ray structures of TvCyP2 were determined under various conditions, all showing the N-terminal segment interacting with the active site of a neighboring TvCyP2, an unusual interaction. NMR study revealed that this particular interaction exists in solution as well and also the N-terminal segment seems to interact with the membrane. In vivo study of TvCyP2 and TvCyP2-∆N (TvCyP2 without the N-terminal segment) indicated that both proteins have different subcellular localization. Together, the structural and functional characteristics at the N-terminal segment offer valuable information for insights into the mechanism of how TvCyP2 regulates protein trafficking, which may be applied in drug development to prevent pathogenesis and disease progression in T. vaginalis infection.
Highlights
Cyclophilins (CyPs) are a family of ubiquitous and versatile enzymes found in mammals, bacteria, plants, insects, and fungi [1]
Experiment, the molecular weight of TvCyP2 was measured at ~20.01 kDa in a solution similar to theoretical molecular weight 20.947 kDa (Figure 2A), TvCyP2 forms a monomer, which agrees well with most of the single-domain CyPs but not TvCyP1
Two sets of NMR resonances were detected in the Myb352–59 peptide in the absence of TvCyP2, so the cis/trans interconversion in peptide alone is slow on the NMR time scale (Figure 2B)
Summary
Cyclophilins (CyPs) are a family of ubiquitous and versatile enzymes found in mammals, bacteria, plants, insects, and fungi [1]. Besides peptidyl-prolyl isomerase (PPIase) activity that catalyzes the interconversion of cis/trans isomerization of prolyl peptide bonds [2], CyPs possess multiple biological functions, including protein folding and trafficking, immune response, signal transduction, viral infection, and transcription regulation [1,3,4]. 24 unique CyPs have been identified [5,6]. Human cyclophilin A (hCyPA), a highly abundant protein that makes up 0.1–0.6% of the total cytosolic proteins [7,8], is the extensively studied cyclophilin. HCyPA initially is the primary cytosolic binding protein of cyclic undecapeptide cyclosporine A (CsA), an immunosuppressive drug [9,10]. HCyPA may be a potential target for antiviral therapy because it interacts with viral capsids, such as SARS-CoV [15,16,17]
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