Molecular mechanisms of parasite motility

Project Leader
Inari Kursula, Ph.D.

Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland and Department of Biomedicine, University of Bergen, Bergen, Norway

Background and Significance

Malaria is one of the most devastating global diseases, affecting the lives of almost half of the world population. The disease is caused by unicellular eukaryotic parasites of the genus Plasmodium, which belong to the phylum Apicomplexa. Apicomplexan parasites use a particular form of motility, termed gliding, to traverse tissues and enter their host cells. Force for gliding is generated by an unconventional actin-myosin motor, which is part of a large membrane-associated protein complex called the glideosome. Most components of the glideosome are known, but detailed molecular mechanisms of how force is generated and transformed into rapid and smooth gliding are not understood. Apicomplexa are early-branched organisms, and our work is aimed at shedding light on the evolutionary relationships of the cytoskeleton and motor proteins in these parasites and higher eukaryotes and comparing the ways in which force is produced for different forms of cell motility. Glideosome proteins, including actin and myosin, are either unique to Apicomplexa or highly divergent from their human counterparts. Thus, they are attractive targets for drug and/or vaccine development. In addition, understanding cell motility at the molecular level enhances our understanding of fundamental cellular processes from development to disease, including many infectious diseases, cardiac and skeletal muscle disorders, and cancer.

Recent Progress

We started the work in 2008, initially by dissecting the Plasmodium actin regulatory machinery into its individual components for structural and biochemical studies. To date, we have determined high-resolution crystal and/or low-resolution solution structures of both Plasmodium actin isoforms and nearly all of the actin regulators. The structures reveal several key differences compared with the canonical higher-eukaryotic proteins. We have also shown (by cryo-EM) that the two parasite actins form different filaments, and that the differences in filament structure are required for the biological functions of the two actins in different life-cycle stages of the parasite. Intriguingly, we discovered that the classical link between ATP hydrolysis and polymerization seems to be broken in Plasmodium actins, which raises interesting questions about the evolution of actin and its polymerization propensity. Our most recent work has been focused on characterizing the mechanism of polymerization and ATP hydrolysis and the structure of the parasite actin filaments at high resolution. In addition, we are now aiming at a more holistic understanding of the entire glideosome, including the motor protein myosin and the membrane (protein) components.

Future Goals

Our future goals and major questions are:

1. Elucidating the structure and mechanism of the entire molecular motor providing force for apicomplexan gliding motility. What does the motor look like? How is force for gliding generated?

2. Understanding the evolution of apicomplexan gliding and that of eukaryotic cell motility in general. Are there significant functional differences in the different actin-myosin motors in Apicomplexa and higher eukaryotes? Is the mechanism of gliding the same in all Apicomplexa? How is speed determined?

3. Understanding the mechanism of ATP hydrolysis and its link to polymerization in apicomplexan actins. How have polymerization propensity and ATP hydrolysis in different actins evolved?

4. Finally, we aim to exploit the differences between the apicomplexan and human actins and their regulatory machineries in rational drug and vaccine design.

Selected Publications

Bhargav SP, Vahokoski J, Kallio JP, Torda A, Kursula P, Kursula I. Two independently folding units of Plasmodium profilin suggest evolution via gene fusion. Cell Mol Life Sci 72:4193-4203, 2015

Kumpula EP & Kursula I. Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies? Acta Cryst F 71:485-499, 2015

Mueller C, Samoo A, Hammoudi PM, Klages N, Kallio JP, Kursula I, Soldati-Favre D. Structural and functional dissection of Toxoplasma gondii armadillo repeats only protein (TgARO). J Cell Sci in press, 2016

Salamun J, Kallio JP, Daher W, Soldati-Favre D, Kursula I. Structure of Toxoplasma gondii coronin – an actin-binding protein that relocalizes to the posterior pole of invasive parasites and contributes to invasion and egress. FASEB J, 28:4729-4747, 2014

Vahokoski J, Bhargav SP, Desfosses A, Andreadaki M, Kumpula EP, Muñico Martinez S, Ignatev A, Lepper S, Frischknecht F, Sidén-Kiamos I, Sachse C, Kursula I. Structural differences explain diverse functions of Plasmodium actins. PLoS Pathog, 10: e1004091, 2014

Doctoral Theses 2015

Moon Chatterjee: Apicomplexan actin depolymerizing factors and capping proteins in the regulation of actin filament dynamics, University of Hamburg, 2015

Nele Vervaet: Structural and functional characterization of profilin from Schistosoma japonicum, University of Hamburg, 2015

Research Group Members

Project Leader:
Inari Kursula, Professor, Ph.D. (Academy of Finland, University of Bergen)

Senior and Post-doctoral Investigators:
Juha Vahokoski, Ph.D. (University of Bergen)
Juha Kallio, Ph.D. (Helse Vest, Bergen)
Yu-Fu Hung, Ph.D. (Sigrid Jusélius foundation, Aca)
Huijong Han, Ph.D. (Biocenter Oulu)
Leila Tajedin, Ph.D. (Jane and Aatos Erkko foundation)
Henni Piirainen, M.Sc. (Emil Aaltonen foundation)

Ph.D. Students:
Esa-Pekka Kumpula, M.Sc. (Academy of Finland)
Atta Samoo, M.Sc. (Higher Education Committee, Pakistan)
Isa Pires, M.Sc. (Biocenter Oulu)
Ábris Bendes, M.Sc. (Biocenter Oulu)
Devaki Lasiwa, M.Sc. (Sigrid Jusélius foundation)

Foreign Scientists:  7

National and International Activities

Group Members Who Spent More Than Two Weeks in Foreign Laboratories During 2015

Inari Kursula, DESY/European XFEL, Hamburg, Germany and University of Bergen, Bergen, Norway
Juha Vahokoski, University of Bergen, Bergen, Norway
Juha Kallio, DESY/European XFEL, Hamburg, Germany and University of Bergen, Bergen, Norway
Esa-Pekka Kumpula, DESY, Hamburg, Germany
Atta Samoo, DESY, Hamburg, Germany

Co-operation With Finnish and Foreign Companies

European XFEL GmbH, Hamburg, Germany, developing methods and building a sample environment for biological sample preparation for X-ray free-electron laser experiments

Last updated: 11/10/2016