The apicomplexan glideosome and adhesins – Structures and function

Abstract

The apicomplexan family of pathogens, which includes Plasmodium spp. and Toxoplasma gondii, are primarily obligate intracellular parasites and invade multiple cell types. These parasites express extracellular membrane protein receptors, adhesins, to form specific pathogen-host cell interaction complexes. Various adhesins are used to invade a variety of cell types. The receptors are linked to an actomyosin motor, which is part of a complex comprised of many proteins known as the invasion machinery or glideosome. To date, reviews on invasion have focused primarily on the molecular pathways and signals of invasion, with little or no structural information presented. Over 75 structures of parasite receptors and glideosome proteins have been deposited with the Protein Data Bank. These structures include adhesins, motor proteins, bridging proteins, inner membrane complex and cytoskeletal proteins, as well as co-crystal structures with peptides and antibodies. These structures provide information regarding key interactions necessary for target receptor engagement, machinery complex formation, how force is transmitted, and the basis of inhibitory antibodies. Additionally, these structures can provide starting points for the development of antibodies and inhibitory molecules targeting protein-protein interactions, with the aim to inhibit invasion. This review provides an overview of the parasite adhesin protein families, the glideosome components, glideosome architecture, and discuss recent work regarding alternative models.

Gliding motility powers invasion and egress in Apicomplexa

“…Compellingly, the cytoplasmic tail moieties of several conserved adhesins, such as the micronemal proteins MIC2, TRAP and apical membrane antigen 1 (AMA1), as well as PfRH family members, were shown to bind to ALD, mainly in vitro 88 . In addition, TgALD-depleted T. gondii parasites showed a defect in motility and invasion, and a substantial loss of fitness 89 .…”

The development of malaria parasites in the mosquito midgut

“…Gametocytes possess an inner membrane complex (IMC) underneath their plasmalemma, which consists of flat membranous sacs, the alveoli, and supporting structural elements and which is thought to be required for the stability of the crescent‐shaped parasite stages (Dearnley et al ., 2012; Kono et al ., 2012; Simon et al ., 2013; reviewed in Harding and Meissner, 2014; Boucher and Bosch, 2015). During gametogenesis, the IMC disintegrates, resulting in gametes solely confined by the plasmalemma.…”

Gliding motility in apicomplexan parasites

“…A numberof biochemical, mutational and structural analyseshave characterized the interactions among the adhesin tails,aldolase and actin [94,113,114,[117][118][119] and consistently reinforced the role of aldolase as the linking molecule between the adhesins and the cytoskeletal apparatus.Recently, however, the essential role of aldolase has been reexamined and evidence presented that it is dispensable for parasite motility [112].Parasites expressing mutant forms of aldolase, or subject to depleted levels of aldolase, were still capable of normal gliding and invasive motilitywhen grown in a glucosefree medium that prevented the generation of toxic metabolites and the subsequent cellular impairments seen in cells cultured in glucose-rich media [112]. These results suggest that the primary role of aldolase is not in linking adhesins to the cytoskeletal motor complex, but rather in normal cellular metabolism [112].…”

“…Nevertheless, it is ofsome interest to explore the mechanism by which such a drasticallyimpaired cell can still compensate, albeit with greatly reduced efficiency. As noted by Boucher and Bosch [94], the actin-related proteins, which still remain largely uncharacterized in the Apicomplexa [95], mightoffer sufficient functional redundancyto provide some marginalcompensation for the loss of parasite actin. Alternatively, as proposed by Egarter et al [67], the cell might employ a completely different mode of locomotion to accomplish its goals.…”

“…While an exploration of such alternative mechanisms will, no doubt, enhance our understanding of parasite biology, the primacy of actin in normal gliding motility is clear. [94,[96][97][98].Disruption of these proteins can lead to variable impairmentsin substrate attachment and motor-generated activities including gliding, host cell traversal and host cell invasion [41,[99][100][101][102][103][104][105].…”