Interaction of Plasmodium falciparum apicortin with α- and β-tubulin is critical for parasite growth and survival

Abstract

Cytoskeletal structures of Apicomplexan parasites are important for parasite replication, motility, invasion to the host cell and survival. Apicortin, an Apicomplexan specific protein appears to be a crucial factor in maintaining stability of the parasite cytoskeletal assemblies. However, the function of apicortin, in terms of interaction with microtubules still remains elusive. Herein, we have attempted to elucidate the function of Plasmodium falciparum apicortin by monitoring its interaction with two main components of parasite microtubular structure, α-tubulin-I and β-tubulin through in silico and in vitro studies. Further, a p25 domain binding generic drug Tamoxifen (TMX), was used to disrupt PfApicortin-tubulin interactions which led to the inhibition in growth and progression of blood stage life cycle of P. falciparum.

Apicortin, a Constituent of Apicomplexan Conoid/Apical Complex and Its Tentative Role in Pathogen—Host Interaction

“…Immuno-localization of apicortin was monitored in various stages of P. falciparum [ 44 , 45 ]. Apicortin was localized on the surface of the parasite in the subpellicular region of both the trophozoites and the schizonts, where apicortin was co-localized with merozoite surface protein 1 (MSP1) and myosin A tail interacting protein (MTIP).…”

“…It was co-localized with both α- and β-tubulin. The localization of apicortin was confirmed in the nuclear and cytoplasmic extracts of the parasite with a major occurrence in the cytoplasm [ 44 , 45 ] ( Table 1 ).…”

“…Interaction of P. falciparum apicortin with P. falciparum tubulin was demonstrated by in silico docking studies, which have revealed that partial p25 domain residues present on the surface of apicortin are involved in the binding to both α- and β-tubulin [ 44 ]. It is worth noting that the partial p25alpha domain of P. falciparum is somewhat different from that of the other apicomplexans (cf.…”

“…The role of this domain in the binding coincides with the finding by Leung et al [ 28 ] who described the same for the apicortin-tubulin interaction in T. gondii . The binding was confirmed experimentally in vitro by immunological (immunoprecipitation, ELISA) and binding (surface plasmon resonance-SPR) methods as well as by a tubulin polymerization assay [ 44 ]. Interestingly, in contrast to T. gondii apicortin [ 28 ], the recombinant protein of P. falciparum expressed in E. coli could be successfully purified.…”

“…Apicortin expression was ~30% reduced in miRNA-loaded erythrocytes. Downregulation of apicortin by miR-197 resulted in loss of the organized structure of tubulin as demonstrated by the diffuse immunostaining of tubulin [ 44 ]. Growth of the parasite was hindered, and the rate of invasion decreased significantly.…”