A function of profilin in force generation during malaria parasite motility that is independent of actin binding.

During transmission of malaria-causing parasites from mosquito to mammal, sporozoites migrate at high speed within the skin to access the bloodstream and infect the liver. This unusual gliding motility is based on retrograde flow of membrane proteins and highly dynamic actin filaments that provide short tracks for a myosin motor. Using laser tweezers and parasite mutants, we previously suggested that actin filaments form macromolecular complexes with plasma membrane-spanning adhesins to generate force during migration.

A unique profilin-actin interface is important for malaria parasite motility.

Profilin is an actin monomer binding protein that provides ATP-actin for incorporation into actin filaments. In contrast to higher eukaryotic cells with their large filamentous actin structures, apicomplexan parasites typically contain only short and highly dynamic microfilaments. In apicomplexans, profilin appears to be the main monomer-sequestering protein.

Two independently folding units of Plasmodium profilin suggest evolution via gene fusion.

Gene fusion is a common mechanism of protein evolution that has mainly been discussed in the context of multidomain or symmetric proteins. Less is known about fusion of ancestral genes to produce small single-domain proteins. Here, we show with a domain-swapped mutant Plasmodium profilin that this small, globular, apparently single-domain protein consists of two foldons.

Structural differences explain diverse functions of Plasmodium actins.

Actins are highly conserved proteins and key players in central processes in all eukaryotic cells. The two actins of the malaria parasite are among the most divergent eukaryotic actins and also differ from each other more than isoforms in any other species. Microfilaments have not been directly observed in Plasmodium and are presumed to be short and highly dynamic.

Crystallization and preliminary structural characterization of the two actin isoforms of the malaria parasite.

Malaria is a devastating disease caused by apicomplexan parasites of the genus Plasmodium that use a divergent actin-powered molecular motor for motility and invasion. Plasmodium actin differs from canonical actins in sequence, structure and function. Here, the purification, crystallization and secondary-structure analysis of the two Plasmodium actin isoforms are presented.

Juxtanodin is an intrinsically disordered F-actin-binding protein.

Juxtanodin, also called ermin, is an F-actin-binding protein expressed by oligodendrocytes, the myelin-forming cells of the central nervous system. While juxtanodin carries a short conserved F-actin-binding segment at its C terminus, it otherwise shares no similarity with known protein sequences. We carried out a structural characterization of recombinant juxtanodin in solution.

The lasso segment is required for functional dimerization of the Plasmodium formin 1 FH2 domain.

Apicomplexan parasites, such as the malaria-causing Plasmodium species, utilize a unique way of locomotion and host cell invasion. This substrate-dependent gliding motility requires rapid cycling of actin between the monomeric state and very short, unbranched filaments. Despite the crucial role of actin polymerization for the survival of the malaria parasite, the majority of Plasmodium cellular actin is present in the monomeric form.

X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition.

Triclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2' substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan.

Crystallization and preliminary structural characterization of the two actin-depolymerization factors of the malaria parasite.

The malaria parasite Plasmodium depends on its actin-based motor system for motility and host-cell invasion. Actin-depolymerization factors are important regulatory proteins that affect the rate of actin turnover. Plasmodium has two actin-depolymerization factors which seem to have different functions and display low sequence homology to the higher eukaryotic family members.