skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?

Abstract

In this review, current structural understanding of the apicomplexan glideosome and actin regulation is described. Apicomplexan parasites are the causative agents of notorious human and animal diseases that give rise to considerable human suffering and economic losses worldwide. The most prominent parasites of this phylum are the malaria-causing Plasmodium species, which are widespread in tropical and subtropical regions, and Toxoplasma gondii, which infects one third of the world’s population. These parasites share a common form of gliding motility which relies on an actin–myosin motor. The components of this motor and the actin-regulatory proteins in Apicomplexa have unique features compared with all other eukaryotes. This, together with the crucial roles of these proteins, makes them attractive targets for structure-based drug design. In recent years, several structures of glideosome components, in particular of actins and actin regulators from apicomplexan parasites, have been determined, which will hopefully soon allow the creation of a complete molecular picture of the parasite actin–myosin motor and its regulatory machinery. Here, current knowledge of the function of this motor is reviewed from a structural perspective.

Authors:
 [1];  [2];  [2];  [1];  [2];  [2];  [3]
  1. University of Oulu, PO Box 3000, 90014 Oulu (Finland)
  2. (Germany)
  3. (Norway)
Publication Date:
OSTI Identifier:
22375718
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta crystallographica. Section F, Structural biology communications; Journal Volume: 71; Journal Issue: Pt 5; Other Information: PMCID: PMC4427158; PMID: 25945702; PUBLISHER-ID: hv5284; PUBLISHER-ID: S2053230X1500391X; OAI: oai:pubmedcentral.nih.gov:4427158; Copyright (c) Kumpula & Kursula 2015; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CURRENTS; DESIGN; LOSSES; MICROTUBULES; PLASMA; REVIEWS

Citation Formats

Kumpula, Esa-Pekka, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, Kursula, Inari, E-mail: inari.kursula@helmholtz-hzi.de, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, and University of Bergen, Jonas Lies vei 91, 5009 Bergen. Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?. United States: N. p., 2015. Web. doi:10.1107/S2053230X1500391X.
Kumpula, Esa-Pekka, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, Kursula, Inari, E-mail: inari.kursula@helmholtz-hzi.de, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, & University of Bergen, Jonas Lies vei 91, 5009 Bergen. Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?. United States. doi:10.1107/S2053230X1500391X.
Kumpula, Esa-Pekka, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, Kursula, Inari, E-mail: inari.kursula@helmholtz-hzi.de, Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg, German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg, and University of Bergen, Jonas Lies vei 91, 5009 Bergen. Thu . "Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?". United States. doi:10.1107/S2053230X1500391X.
@article{osti_22375718,
title = {Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?},
author = {Kumpula, Esa-Pekka and Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg and German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg and Kursula, Inari, E-mail: inari.kursula@helmholtz-hzi.de and Helmholtz Centre for Infection Research, Notkestrasse 85, 22607 Hamburg and German Electron Synchrotron, Notkestrasse 85, 22607 Hamburg and University of Bergen, Jonas Lies vei 91, 5009 Bergen},
abstractNote = {In this review, current structural understanding of the apicomplexan glideosome and actin regulation is described. Apicomplexan parasites are the causative agents of notorious human and animal diseases that give rise to considerable human suffering and economic losses worldwide. The most prominent parasites of this phylum are the malaria-causing Plasmodium species, which are widespread in tropical and subtropical regions, and Toxoplasma gondii, which infects one third of the world’s population. These parasites share a common form of gliding motility which relies on an actin–myosin motor. The components of this motor and the actin-regulatory proteins in Apicomplexa have unique features compared with all other eukaryotes. This, together with the crucial roles of these proteins, makes them attractive targets for structure-based drug design. In recent years, several structures of glideosome components, in particular of actins and actin regulators from apicomplexan parasites, have been determined, which will hopefully soon allow the creation of a complete molecular picture of the parasite actin–myosin motor and its regulatory machinery. Here, current knowledge of the function of this motor is reviewed from a structural perspective.},
doi = {10.1107/S2053230X1500391X},
journal = {Acta crystallographica. Section F, Structural biology communications},
number = Pt 5,
volume = 71,
place = {United States},
year = {Thu Apr 16 00:00:00 EDT 2015},
month = {Thu Apr 16 00:00:00 EDT 2015}
}
  • Throughout their life, plants typically remain in one location utilizing sunlight for the synthesis of carbohydrates, which serve as their sole source of energy as well as building blocks of a protective extracellular matrix, called the cell wall. During the course of evolution, plants have repeatedly adapted to their respective niche,which is reflected in the changes of their body plan and the specific design of cell walls. Cell walls not only changed throughout evolution but also are constantly remodelled and reconstructed during the development of an individual plant, and in response to environmental stress or pathogen attacks. Carbohydrate-rich cell wallsmore » display complex designs, which together with the presence of phenolic polymers constitutes a barrier for microbes, fungi, and animals. Throughout evolution microbes have co-evolved strategies for efficient breakdown of cell walls. Our current understanding of cell walls and their evolutionary changes are limited as our knowledge is mainly derived from biochemical and genetic studies, complemented by a few targeted yet very informative imaging studies. Comprehensive plant cell wall models will aid in the re-design of plant cell walls for the purpose of commercially viable lignocellulosic biofuel production as well as for the timber, textile, and paper industries. Such knowledge will also be of great interest in the context of agriculture and to plant biologists in general. It is expected that detailed plant cell wall models will require integrated correlative multimodal, multiscale imaging and modelling approaches, which are currently underway.« less
  • No abstract prepared.
  • Highlights: Black-Right-Pointing-Pointer Engineered kinesin-M13 and calmodulin involving single cysteine were prepared. Black-Right-Pointing-Pointer CaM mutant was cross-linked to dimer by bifunctional thiol reactive reagent. Black-Right-Pointing-Pointer Kinesin-M13 was dimerized via CaM dimer in the presence of calcium. Black-Right-Pointing-Pointer Function of the engineered kinesin was regulated by a Ca{sup 2+}-calmodulin dimer linker. -- Abstract: The kinesin-microtubule system holds great promise as a molecular shuttle device within biochips. However, one current barrier is that such shuttles do not have 'on-off' control of their movement. Here we report the development of a novel molecular motor powered by an accelerator and brake system, using a kinesinmore » monomer and a calmodulin (CaM) dimer. The kinesin monomer, K355, was fused with a CaM target peptide (M13 peptide) at the C-terminal part of the neck region (K355-M13). We also prepared CaM dimers using CaM mutants (Q3C), (R86C), or (A147C) and crosslinkers that react with cysteine residues. Following induction of K355-M13 dimerization with CaM dimers, we measured K355-M13 motility and found that it can be reversibly regulated in a Ca{sup 2+}-dependent manner. We also found that velocities of K355-M13 varied depending on the type and crosslink position of the CaM dimer used; crosslink length also had a moderate effect on motility. These results suggest Ca{sup 2+}-dependent dimerization of K355-M13 could be used as a novel molecular shuttle, equipped with an accelerator and brake system, for biochip applications.« less
  • Highlights: •Tamoxifen produces cytotoxicity via estrogen-receptor (ER) independent mechanisms. •Tamoxifen binds to CB1 and CB2 cannabinoid receptors and acts as an inverse agonist. •CB1 and CB2 receptors are novel molecular targets for Tamoxifen. •ER-independent effects for Tamoxifen may be mediated via CB1 and/or CB2 receptors. -- Abstract: Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam canmore » produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9–3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs.« less