Apicortin was identified in silico, in 2009, as a characteristic protein of apicomplexans. It combines a partial p25alpha domain with a DCX (doublecortin) one. Based on its occurrence and one of its characteristic domains, it was termed apicortin. Apicortin, when identified, was shown to occur in apicomplexan parasites and in the placozoan animal, Trichoplax adhaerens. The apicomplexan genomes known then contained it without exception. This situation practically has not changed since then; this statement is valid for the newly sequenced genomes and transcriptomes of apicomplexans as well, almost without exception.
In 2009, apicortin was identified in silico as a characteristic protein of apicomplexans that also occurs in the placozoa, Trichoplax adhaerens. Since then, it has been found that apicortin also occurs in free-living cousins of apicomplexans (chromerids) and in flagellated fungi. It contains a partial p25-α domain and a doublecortin (DCX) domain, both of which have tubulin/microtubule binding properties. Apicortin has been studied experimentally in two very important apicomplexan pathogens, Toxoplasma gondii and Plasmodium falciparum. It is localized in the apical complex in both parasites. In T. gondii, apicortin plays a key role in shaping the structure of a special tubulin polymer, conoid. In both parasites, its absence or downregulation has been shown to impair pathogen–host interactions. Based on these facts, it has been suggested as a therapeutic target for treatment of malaria and toxoplasmosis.
Apicortin was identified in silico, in 2009, as a characteristic protein of apicomplexans. It combines a partial p25alpha domain with a DCX (doublecortin) one. Based on its occurrence and one of its characteristic domains, it was termed apicortin. In T. gondii it is also known as TgDCX .
Apicortins consist of four structural units: (i) a long, disordered N-terminal domain; (ii) a partial p25alpha domain; (iii) a disordered linker region; (iv) and a DCX domain.
The N-terminal part consists of about 70–90 amino acids in apicomplexan apicortins, similarly to the apicortins of the few non-flagellated fungi; this part is 40 amino acid long in one of the C. velia apicortins (Cvel_6797) while in other species (placozoa, chromerids, flagellated fungi) it is absent. The N-terminus of the proteins is rather different among the various apicomplexan species. It is not conserved among the species belonging to different classes of Apicomplexa, or the various genera of the same class, or even among the various Plasmodium subgenera. The extra N-terminal regions are significantly similar in the two fungal apicortins possessing it. Concerning the secondary structure, the N-terminal region of apicortins was shown to be highly disordered by predictor programs based on different principles.
The partial p25alpha domain, in general, is the most conservative part of the protein, however, there are two exceptions. R. allomycis and Plasmodium orthologs present in species infecting mammals (but not birds) lack the final part of this domain, which includes the Rossmann-like motif. Otherwise, the sequences are very similar, independently of whether the protein can be found in an apicomplexan species or not. It was shown by Leung et al. that this region of the protein has an outstanding role in tubulin binding.
In the linker (interdomain) region, which has also been predicted to be unstructured, similarity is much lower between protist and non-protist apicortins. Moreover, this part of Plasmodium proteins also differs somewhat from those of the other apicomplexan orthologs.
In the DCX domain, the overall similarity is somewhat lower between the two groups than in the case of the partial p25alpha domain; however, there is no exception: the similarity occurs through the whole domain in all orthologs. Phylogenetic analysis showed that DCX domains of apicortins are clustered neither with C- nor N-terminal type domains but form a separate group.
Phylogenetic analysis clearly showed that apicomplexan apicortins form a monophyletic group and are well separated from opisthokont (fungal and placozoan) and chromerid apicortins. One pair of the chromerid apicortins is a sister group to them, the other 2-2 chromerid homologs are significantly different.
Apicortin is a characteristic protein of Apicomplexa. It is present in both classes, Aconoidasida and Conoidasida, and in each order and family whose species are fully sequenced. According to the NCBI website, 66 genomes of apicomplexan species have been fully sequenced, 65 of which contain apicortin. The only exception, B. microti has a significantly decreased genome which is the smallest one in the phylum. However, it contains a p25alpha domain containing protein, a short-type TPPP (XP_012649535).
The genomes of most Plasmodium species have been sequenced (21), due to their epidemiological significance, followed by 15 sequenced Cryptosporidium species genomes. Apicomplexans are obligate parasites causing serious illnesses in humans and domestic animals. Species in the genus Plasmodium cause malaria, from which over 200 million people suffer each year. The official deaths according to WHO were about 400,000 both in 2018 and 2019. Other members of the phylum Apicomplexa are responsible for animal sicknesses, such as coccidiosis and babesiosis, resulting in significant economic burden for animal husbandry. Cryptosporidium causes cryptosporidiosis in humans and animals, Theileria causes tropical theileriosis and East Coast fever in cattle, and Toxoplasma causes toxoplasmosis in immunocompromised patients and congenitally infected fetuses. The disease-causing parasites belong to the orders Haemosporida, Piroplasmida and Eucoccidiorida, which explains the bias in genome sequencing.
Apicomplexans are an ancient and diverse phylum with peculiar cell biological properties. Many of the distinct traits are related to the unique cytoskeletal elements of these parasites. In addition to microtubules, the main cytoskeletal constituents, several apicomplexans possess another polymer form of tubulin, the conoid that has an important role in host cell invasion. The conoid fibers resemble microtubules but their subunits are curled into an extremely tight coil, where tubulin is arranged into a polymer form that is different from typical microtubules. In T. gondii, apicortin is only localized at the conoid as shown by immunofluorescence staining and the labeling suggested that it is distributed all along the conoid fibers; moreover, apicortin is essential for providing the correct structure and function of conoid. In P. falciparum, which has no conoid, apicortin was observed at the apical end of the parasite suggesting its role in apical complex formation. It was co-localized with both α- and β-tubulin. In both species, downregulation of apicortin leads to impaired host cell invasion. Moreover, apicortin knockout T. gondii grew about four times slower compared with the wild-type ones.