Abstract
Apicomplexan parasites, such as Plasmodium spp., rely on an unusual actomyosin motor, termed glideosome, for motility and host cell invasion. The actin filaments are maintained by a small set of essential regulators, which provide control over actin dynamics in the different stages of the parasite life cycle. Actin filament capping proteins (CPs) are indispensable heterodimeric regulators of actin dynamics. CPs have been extensively characterized in higher eukaryotes, but their role and functional mechanism in Apicomplexa remain enigmatic. Here, we present the first crystal structure of a homodimeric CP from the malaria parasite and compare the homo- and heterodimeric CP structures in detail. Despite retaining several characteristics of a canonical CP, the homodimeric Plasmodium berghei (Pb)CP exhibits crucial differences to the canonical heterodimers. Both homo- and heterodimeric PbCPs regulate actin dynamics in an atypical manner, facilitating rapid turnover of parasite actin, without affecting its critical concentration. Homo- and heterodimeric PbCPs show partially redundant activities, possibly to rescue actin filament capping in life cycle stages where the β-subunit is downregulated. Our data suggest that the homodimeric PbCP also influences actin kinetics by recruiting lateral actin dimers. This unusual function could arise from the absence of a β-subunit, as the asymmetric PbCP homodimer lacks structural elements essential for canonical barbed end interactions suggesting a novel CP binding mode. These findings will facilitate further studies aimed at elucidating the precise actin filament capping mechanism in Plasmodium.
Highlights
Alongside other members of the vast phylum of Apicomplexa, the unicellular parasites responsible for malaria (Plasmodium spp.) use a special actomyosin motor, the glideosome, for motility and host cell invasion during their complex life cycle [1]
capping proteins (CPs) play a crucial role in actin dynamics by binding to the fast-growing barbed end of filamentous actin (F-actin) with high affinity in a Ca2+-independent manner [25], limiting protomer exchange to the pointed end
PbCPα forms homodimers (PbCPαα), capable of capping homologous PfActI [43] and heterologous β-actin filaments in the absence of the α-tentacle [23]. These results suggest that the insect cell stages are regulated by the heterodimeric form, while the pathogenic blood stages are governed by PbCPα, perhaps in a homodimeric form [23, 43]
Summary
Alongside other members of the vast phylum of Apicomplexa, the unicellular parasites responsible for malaria (Plasmodium spp.) use a special actomyosin motor, the glideosome, for motility and host cell invasion during their complex life cycle [1]. Unlike other Apicomplexa, Plasmodium parasites encode two non-canonical actin isoforms [2, 3]. In Plasmodium falciparum, the causative agent of the most deadly form of malaria in humans, actin isoform I (PfActI) is constitutively expressed, encompassing the complete parasite life cycle [4]. CPs are essential for human and zebrafish morphogenesis [29] and belong to the core set of proteins needed to reconstitute actin-based motility in vitro [30]. The average cytosolic concentration of CP in eukaryotes is in the range of 0.5–1.5 μM [31, 32], which, considering the high affinity and 1:1 stoichiometry of CP towards actin filaments, leads to a high number of constantly capped barbed ends in vivo [32]. Steric and allosteric regulators of CPs include polyphosphoinositides (PIPs), V-1/myotrophin, and CARMIL proteins, while indirect barbed end competitors include formins and ENA/VASP proteins [24]
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