Alladi Ramakrishnan Hall

Understanding the differences in Rabbit and Plasmodium actin filament dynamics: Implications for antimalarial drug design

Prajwal Nandekar

Center for Molecular Biology (ZMBH), Heidelberg University, Germany

Malaria is a devastating infectious disease, result in over 400,000 deaths per annum, caused by infection by Plasmodium sp., a parasite with a complex life cycle between mosquito and human. In light of emerging parasite drug resistance, there is a growing need to develop new antimalarial therapies that can kill the malaria parasite at multiple stages of its life cycle. The malaria parasite is able to actively invade and traverse a variety of tissues during its life cycle, including both mosquito stage and human stages [1]. Plasmodium sp. displays an uncommon form of locomotion known as gliding motility, whereby the force of an actin-myosin motor is transmitted through associated transmembrane adhesions to the substrate. Actin is one of the important proteins involved in cell motility machinery. As compared to canonical mammalian actins, which typically form long and stable filaments (of ~15 µm length), Plasmodium actin filaments are shorter (~100 nm), inherently unstable, undergo rapid turnover, and have fundamentally different overall architectures [2]. These differences are crucial for efficient parasite motility. Interestingly, the amino acid sequences of rabbit and Plasmodium actin possess 80% sequence identity and a few residues are different in both species. These residue-level differences give us an excellent opportunity to study structure-function relationships of actin filaments, their implications on parasite mechanobiology, and can be exploited for design and development of parasite specific drug candidates against parasitic diseases like malaria, leishmaniasis [3] and other diseases such as cancer and glaucoma.

Here, we developed a protocol to model atomic-detailed actin filaments using molecular modeling, multi-scale molecular dynamics simulations, and experimental approaches to investigate whether a few non-conserved residues in contact regions between the filament subunits are the primary contributors to differences in structure of filaments and motility in a parasite and a human [4]. As an outcome of our studies, we have identified several residues in actin which are crucial for the differential properties of actin filament, and parasite motility. These residues can be targeted for rational drug design against parasitic diseases.

References:
1. Douglas R, et al. (2015) Trends Parasitol., 31(8), 357-362.
2. Vahokoski J, et al. (2014) PLoS Pathog., 10(4): e1004091.
3. García-Salcedo JA, et al. (2004) EMBO J., 23, 780-789.
4. Douglas R, Nandekar P, et al. (2018) PLoS Biology, 16 (7), e2005345.