Comparative Genomic and Phylogenetic Analyses of Calcium ATPases and Calcium-Regulated Proteins in the Apicomplexa

Abstract

The phylum Apicomplexa comprises a large group of early branching eukaryotes that includes a number of human and animal parasites. Calcium controls a number of vital processes in apicomplexans including protein secretion, motility, and differentiation. Despite the importance of calcium as a second messenger, very little is known about the systems that control homeostasis or that regulate calcium signaling in parasites. The recent completion of many apicomplexan genomes provides new opportunity to define calcium response pathways in this group of parasites in comparison to model organisms. Whole-genome comparison between the apicomplexans Plasmodium spp., Cryptosporidium spp., and Toxoplasma gondii revealed the presence of several P-Type Ca2+ transporting ATPases including a single endoplasmic reticulum (ER)-type sarcoplasmic-endoplasmic reticulum Ca2+ ATPase, several Golgi-like Ca2+ ATPases, and a single Ca2+/H+ exchanger. Only T. gondii showed evidence of plasma membrane-type Ca2+ ATPases or voltage-gated calcium channels. Despite pharmacological evidence for IP3 and ryanodine-mediated calcium release, animal-type calcium channels were not readily identified in parasites, indicating they are more similar to plants. Downstream of calcium release, a variety of EF-hand-containing proteins regulate calcium responses. Our analyses detected a single conserved calmodulin (CaM) homologue, 3 distinct centrin (CETN)-caltractin-like proteins, one of which is shared with ciliates, and a variety of deep-branching, CaM-CETN-like proteins. Apicomplexans were also found to contain a wide array of calcium-dependent protein kinases (CDPKs), which are commonly found in plants. Toxoplasma gondii contains more than 20 CDPK or CDPK-related kinases, which likely regulate a variety of responses including secretion, motility, and differentiation. Genomic and phylogenetic comparisons revealed that apicomplexans contain a variety of unusual calcium response pathways that are distinct from those seen in vertebrates. Notably, plant-like pathways for calcium release channels and calcium-dependent kinases are found in apicomplexans. The experimental flexibility of T. gondii should allow direct experimental manipulation of these pathways to validate their biological roles. The central importance of calcium in signaling and development, and the novel characteristics of many of these systems, indicates that parasite calcium pathways may be exploited as new therapeutic targets for intervention.

Unfolding the secrets of coral–algal symbiosis

“…In the Apicomplexa, Ca 2 þ acts as a secondary messenger via a range of calcium-dependent protein kinases, and initiates a number of signaling processes that are important for communication between eukaryotic cells (Nagamune and Sibley, 2006). Calcium signaling and calcium-regulated protein kinases have also been recognized for their critical role in establishing plant-microbe symbioses, especially in the plant-rhizobium system (Harper and Harmon, 2005;Oldroyd et al, 2009).…”

Novel Types of Ca2+ Release Channels Participate in the Secretory Cycle of Paramecium Cells

“…Despite these data, the molecular characterization of IP 3 or ryanodine receptors in low eukaryotes is currently a challenge since the identification of orthologues has not been possible thus far, probably because of evolutionary sequence divergence (66). Traynor et al (96) identified an IP 3 receptor-like protein, IplA, in Dictyostelium discoideum, which possesses regions related to IP 3 R sequences, but thus far no evidence for IP 3 interaction exists.…”

A novelToxoplasma gondiicalcium-dependent protein kinase

“…The biochemical pathways involved in host cell invasion have not been identified, but several lines of evidence suggest that Ca 2+ is important for parasite motility (Mondragon & Frixione, 1996;Smith, 1995;Werk, 1985;Pezella et al, 1997) and the Zhao et al, 1993). T. gondii contains more than 20 CDPK or CDPK-related kinases (Nagamune & Sibley, 2006). In the present, two related T. gondii CDPK isoforms have been recently identified, where TgCDPK1 seems to play a central role in regulating parasite motility and host cell invasion (Kieschnick et al, 2001).…”